Medical Oncology

Nanotheranostics for gynecological cancers: a path forward for Africa

Nanoparticle-based therapies represent a transformative approach to managing gynecological cancers, offering targeted treatment strategies that minimize harm to healthy tissues while maximizing therapeutic efficacy. Despite their potential, implementing these advanced treatments in Africa is needed by a complex interplay of technological, economic, regulatory, and ethical challenges. This paper examines the current landscape of nanoparticle-based therapies, identifying critical barriers to their adoption, including inadequate infrastructure, high costs, and insufficient regulatory frameworks. Technological deficiencies manifest as a need for advanced nanoparticle synthesis, delivery, and diagnostics equipment, impeding research and clinical applications. Economically, the high production costs of nanoparticles, compounded by limited access to advanced diagnostic and treatment facilities, create significant financial barriers for healthcare systems and patients alike. Additionally, the regulatory environment needs to be more cohesive, characterized by a lack of established protocols and expertise to evaluate the unique properties of nanomedicines. However, opportunities for advancement exist through focused research and development initiatives. Targeted drug delivery systems, early detection methods, and immunotherapy integration are promising avenues to enhance treatment outcomes. Collaborative partnerships between African institutions and international research entities, alongside public-private collaborations, could bolster local capabilities in nanomedicine. To facilitate the integration of nanoparticle-based therapies, African governments must prioritize funding for nanomedicine research, create robust regulatory frameworks, and ensure equitable access to these innovative treatments. A concerted effort involving policy reforms, investment, and collaboration is essential for overcoming existing barriers and realizing the full potential of nanoparticle-based therapies in improving health outcomes for gynecological cancer patients across Africa.

Photodynamic therapy boosts the anti-proliferative activity of oxaliplatin in cervical cancer cells by regulating stemness-related genes

Cervical cancer is the fourth most prevalent cancer among women worldwide and remains a significant contributor to cancer-related mortality, particularly in low- and middle-income countries, largely due to treatment resistance and disease recurrence. Growing evidence indicates that cancer stem cells (CSCs) play a pivotal role in tumor initiation, progression, and therapeutic resistance. Consequently, the development of novel therapeutic strategies capable of eliminating cancer cells while simultaneously targeting CSC-associated pathways holds substantial clinical promise. This study aimed to evaluate the combined effects of zinc phthalocyanine-mediated photodynamic therapy (ZnPc-PDT) combined with oxaliplatin on cervical cancer cells. The focus was on assessing cell viability, apoptosis, colony formation, migration, stemness characteristics, and the expression of key genes involved in CSC regulation. Human cervical cancer cell lines (HeLa and Caski) were treated with ZnPc-PDT, oxaliplatin, or their combination. Cytotoxicity was measured using MTT assays, while apoptosis was evaluated by Annexin V/PI flow cytometry and expression profiling of apoptosis-related genes (CASPASE3, CASPASE8, CASPASE9, BCL2). Colony-forming assays were used to assess stemness potential, and wound-healing assays evaluated cell migration. Quantitative real-time PCR (qRT-PCR) was performed to examine the expression of stemness-related markers (SOX2, OCT4, CD133, CD44) and metastasis-associated genes (MMP2, MMP9, ROCK1). Additionally, in silico pathway analysis using TCGA-CESC, STRING, and Enrichr datasets identified oxaliplatin-targeted genes involved in CSC regulation and validated the experimental observations. Human cervical cancer cell lines (HeLa and Caski) were treated with ZnPc-PDT, oxaliplatin, or their combination. Cytotoxicity was measured using MTT assays, while apoptosis was evaluated by Annexin V/PI flow cytometry and expression profiling of apoptosis-related genes (CASPASE3, CASPASE8, CASPASE9, BCL2). Colony-forming assays were used to assess stemness potential, and wound-healing assays evaluated cell migration. Quantitative real-time PCR (qRT-PCR) was performed to examine the expression of stemness-related markers (SOX2, OCT4, CD133, CD44) and metastasis-associated genes (MMP2, MMP9, ROCK1). Additionally, in silico pathway analysis using TCGA-CESC, STRING, and Enrichr datasets identified oxaliplatin-targeted genes involved in CSC regulation and validated the experimental observations. The combination of ZnPc-PDT and oxaliplatin exhibits potent anti-cancer effects by inducing apoptosis, suppressing migration, reducing stemness, and modulating key cancer-related pathways. By integrating molecular experiments with in silico analysis, this study provides mechanistic insights into how PDT enhances oxaliplatin efficacy. These findings suggest that ZnPc-PDT combined with oxaliplatin may represent a promising therapeutic strategy to overcome drug resistance and reduce recurrence in cervical cancer treatment.

A randomized clinical trial assessing the efficacy of vitamin B prophylaxis in attenuating paclitaxel-induced neuropathy and the imperative use of gabapentin in diabetic ovarian cancer patients

Recent advancement of nanomedicine-based targeted delivery for cervical cancer treatment

Cervical cancer is a huge worldwide health burden, impacting women in impoverished nations in particular. Traditional therapeutic approaches, such as surgery, radiation therapy, and chemotherapy, frequently result in systemic toxicity and ineffectiveness. Nanomedicine has emerged as a viable strategy for targeted delivery of therapeutic drugs to cancer cells while decreasing off-target effects and increasing treatment success in recent years. Nanomedicine for cervical cancer introduces several novel aspects that distinguish it from previous treatment options such as tailored delivery system, precision targeting, combination therapies, real-time monitoring and diverse nanocarriers to overcome the limitations of one another. This abstract presents recent advances in nanomedicine-based tailored delivery systems for the treatment of cervical cancer. Liposomes, polymeric nanoparticles, dendrimers, and carbon nanotubes have all been intensively studied for their ability to transport chemotherapeutic medicines, nucleic acids, and imaging agents to cervical cancer cells. Because of the way these nanocarriers are designed, they may cross biological barriers and preferentially aggregate at the tumor site, boosting medicine concentration and lowering negative effects on healthy tissues. Surface modification of nanocarriers with targeting ligands like antibodies, peptides, or aptamers improves specificity for cancer cells by identifying overexpressed receptors or antigens on the tumor surface. Furthermore, nanomedicine-based techniques have made it possible to co-deliver numerous therapeutic drugs, allowing for synergistic effects and overcoming drug resistance. In preclinical and clinical investigations, combination treatments comprising chemotherapeutic medicines, gene therapy, immunotherapy, and photodynamic therapy have showed encouraging results, opening up new avenues for individualized and multimodal treatment regimens. Furthermore, the inclusion of contrast agents and imaging probes into nanocarrier systems has enabled real-time monitoring and imaging of treatment response. This enables the assessment of therapy efficacy, the early diagnosis of recurrence, and the optimization of treatment regimens.

Silencing KMT2A with siRNA induces apoptosis and cell cycle arrest in high-grade serous ovarian carcinoma cells by modulating GOF p53-dependent pathways, highlighting its potential as a therapeutic target

High-grade serous ovarian carcinoma (HGSOC) is the deadliest gynecological cancer, often characterized by TP53 mutations that result in gain-of-function (GOF) p53, contributing to the aggressive nature of the disease. Recent studies demonstrated that GOF p53 drives cancer progression by recruiting epigenetic regulators that activate the expression of oncogenic genes. One such regulator is lysine methyltransferase 2 A (KMT2A), an enzyme that modulates gene expression by methylating histone H3 at lysine 4. In this study, we explored the expression and functional role of KMT2A in HGSOC progression. The GSE66957 and GSE26712 datasets, along with GeneMANIA and STRING databases, were used to examine KMT2A expression and predict interaction networks in HGSOC. Then, expression levels were validated in ovarian cancer tissues and cell lines via qRT-PCR, western blotting, and immunohistochemistry. KMT2A silencing was achieved using KMT2A-specific siRNA in OVCAR3 cells, with functional impacts on apoptosis and cell cycle progression examined through flow cytometry. The results showed a significant upregulation of KMT2A mRNA and protein levels in HGSOC tissues and cell line. KMT2A knockdown induced cell cycle arrest and apoptosis by modulating cell cycle and apoptotic genes. Moreover, KMT2A silencing significantly reduced GOF p53, YAP, phosphorylated AKT, and their downstream targets, suggesting that KMT2A may cooperate with GOF p53 to promote HGSOC progression via YAP, AKT, and p21 signaling pathways. In conclusion, our data indicate that KMT2A contributes to HGSOC-associated cellular phenotypes in the OVCAR3 model; however, further studies are needed to clarify its broader role in HGSOC and its potential as a therapeutic target.

HPV-associated cancers: insights into the mechanistic scenario and latest updates

Cancer and related diseases are the second leading cause of death worldwide. The human papillomavirus (HPV) is an infectious agent that can be spread mainly through sexual contact and has been linked to several malignancies in both sexes. HPV is linked to almost all cases of cervical cancer. It is also linked to many head and neck cancer (HNC) cases, especially oropharyngeal cancer. Also, some HPV-related cancers, like vaginal, vulvar, penile, and anal cancers, are related to the anogenital area. Over the past few decades, testing for and preventing cervical cancer has improved, but anogenital cancers are still harder to confirm. HPV16 and HPV18 have been extensively researched due to their significant carcinogenic potential. The products of two early viral genes, E6 and E7, have been identified as playing crucial roles in cellular transformation, as emphasized by biological investigations. The complete characterization of numerous mechanisms employed by E6 and E7 in undermining the regulation of essential cellular processes has significantly contributed to our comprehension of HPV-induced cancer progression. This review focuses on the various types of cancers caused by HPV infection and also sheds light on the signaling cascades involved in the same.

LncRNA TMPO-AS1 aggravates the cisplatin resistance in cervical cancer via miR-140-5p/DNMT1 axis-mediated DNA methylation of KLK10

Cisplatin resistance severely limits the efficacy of chemotherapy for cervical cancer (CC), and its molecular mechanisms remain incompletely understood. While epigenetic alterations such as DNA methylation are recognized as important contributors, the upstream regulatory networks, particularly the role of long non-coding RNAs (lncRNAs), are still unclear. This study aimed to explore novel mechanisms influencing cisplatin resistance in cervical cancer. Cisplatin-resistant CC cells (HeLa and SiHa) were established. A comprehensive approach employing mRNA and lncRNA microarrays, RT-qPCR, methylation-specific PCR (MSP-PCR), chromatin immunoprecipitation, luciferase reporter assays, RNA pull-down, RNA immunoprecipitation, cellular functional assays, and a mouse subcutaneous xenograft tumor model was utilized. The study found that Kallikrein 10 (KLK10) expression was significantly downregulated in cisplatin-resistant CC cells due to promoter hypermethylation mediated by DNA methyltransferase 1 (DNMT1). LncRNA microarray analysis revealed that TMPO-AS1 was the most significantly upregulated lncRNA in resistant cells. Functional assays confirmed that TMPO-AS1 promoted cisplatin resistance, proliferation, migration, and invasion of CC cells. Mechanistically, TMPO-AS1 acted as a competitive endogenous RNA (ceRNA) by sponging miR-140-5p, thereby relieving its inhibitory effect on DNMT1 mRNA, upregulating DNMT1 expression, enhancing KLK10 promoter methylation, and leading to its silencing. In vivo experiments further demonstrated that silencing TMPO-AS1 inhibited tumor growth. This study unveils a novel TMPO-AS1/miR-140-5p/DNMT1/KLK10 regulatory axis that plays a critical role in cisplatin resistance in CC, providing a potential therapeutic target for overcoming chemoresistance.

The tumor-promoting role of methionyl-tRNA synthetase 1 in ovarian cancer and its potential mechanisms

Methionyl-tRNA synthetase 1 (MARS) is an enzyme that belongs to the family of aminoacyl-tRNA synthetases. High levels of MARS have been shown to correlate with a poorer prognosis in a variety of tumor types. However, its specific role and the underlying mechanism in cancer, especially in ovarian cancer, are not well understood. This study aims to investigate the roles and potential mechanisms of MARS in ovarian cancer. Our findings reveal that MARS protein levels are elevated in ovarian cancer tissues, and that high MARS expression is associated with reduced overall survival and progression-free survival. Silencing of MARS significantly inhibited the proliferation, colony formation, migration, and invasion of ovarian cancer cells in vitro and mildly suppressed ovarian tumor growth in vivo. MARS silencing contributes to the upregulation of p53 protein. Moreover, RNA sequencing and subsequent in vitro and in vivo validation showed that the TP53-regulated cell cycle genes and immune-related cell surface receptor and cytokine-encoding genes were downregulated following MARS knockdown, suggesting a potential mechanism for the observed attenuation of tumor progression. Our results suggest MARS as a potential biomarker and therapeutic target in ovarian cancer, highlighting the need for further investigation into its multifaceted role in tumor biology and immune cell function.

Targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer

Cervical cancer (CESC) presents a significant clinical challenge, primarily due to an incomplete understanding of the immunometabolic crosstalk within the tumor microenvironment (TME) and the lack of reliable biomarkers for immunotherapy stratification. Thymidylate synthase (TYMS), a pivotal enzyme in nucleotide synthesis, has been implicated in tumor progression, but its role as an immunometabolic regulator in CESC remains unexplored. Through an integrative approach combining single-cell RNA sequencing (scRNA-seq) of 47,589 cells, bulk transcriptomics, functional assays, and in vivo modeling, we delineated the multifaceted functions of TYMS. scRNA-seq analysis revealed a dynamic shift from CD4 + to exhausted CD8 + T-cell dominance during progression, orchestrated by specific ligand-receptor interactions like PTPRC-MRC1. A robust T cell-associated prognostic signature comprising TYMS, MYO6, SPINT1 and ESD was developed, effectively stratifying patients into distinct risk groups with differential tumor stemness, immune infiltration, and response to immunotherapy. Mechanistically, TYMS silencing promoted tumor stemness, migration, and invasion in vitro via targeting miR-197-3p. Crucially, in immunocompetent micemodel, TYMS knockdown accelerated tumor growth and potently suppressed CD8 + T-cell infiltration, demonstrating its role in promoting immune evasion. Conversely, TYMS overexpression suppressed tumorigenesis. Molecular docking identified Deoxyuridine Monophosphate as a high-affinity inhibitor of TYMS. Our findings demonstrate that targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer, establishing TYMS as a promising therapeutic target.

Investigation of the effect of encapsulating cisplatin with the active compound silibinin in PLGA polymeric nanoparticles on the HeLa cervical cancer cell line

Cisplatin remains one of the most widely used chemotherapeutic agents, yet its clinical efficacy is limited by poor tumor selectivity, dose-dependent toxicity, and the development of resistance. Silibinin, a hydrophobic natural compound with antioxidant and anticancer activity, has been proposed as a complementary agent capable of enhancing therapeutic responses. In this study, poly(lactic-co-glycolic acid) (PLGA) nanoparticles were developed to encapsulate cisplatin and silibinin individually, aiming to improve their stability, sustain release, and enhance cytotoxic activity against HeLa cervical cancer cells. Nanoparticles were synthesized using a modified double-emulsion (W/O/W) solvent evaporation method and characterized for particle size, zeta potential, morphology, encapsulation efficiency, and in vitro release. Silibinin-loaded nanoparticles (F4) and cisplatin-loaded nanoparticles (F7) demonstrated optimal physicochemical properties, with encapsulation efficiencies of 81.2% and 59.4%, respectively. TEM imaging confirmed spherical morphology, and DLS analysis showed particle sizes of 144 nm (silibinin) and 164 nm (cisplatin). In vitro drug release studies performed under physiological (pH 7.4, 37 °C) and tumor-mimicking conditions (pH 5.2, 42 °C) revealed accelerated release at acidic and hyperthermic conditions. Silibinin release increased from 53.77% to 81.95%, while cisplatin release increased from 57.18% to 73.41% under tumor-like conditions. Both formulations exhibited biphasic release behavior consistent with diffusion-controlled kinetics. Cytotoxicity assessment using the MTT assay demonstrated a significant reduction in HeLa cell viability for both optimized formulations, with the combined treatment showing enhanced inhibitory effects compared to individual drugs. Overall, the findings indicate that PLGA nanoparticles can effectively enhance the controlled release and anticancer activity of cisplatin and silibinin, supporting their potential application as a more efficient and less toxic therapeutic strategy for cervical cancer.

EGF induces SOD activity, TNF-α/IL-6 expression and complement regulatory proteins in cervical cancer cells: suppression by EGCG

Human papilloma virus (HPV) infection is known to induce chronic inflammation and trigger oncogenesis. The present study is intended to understand the role of EGF on the secretion of inflammatory cytokines by CC and to assess the anti-inflammatory efficacy of EGCG under basal and EGF-stimulated conditions. EGCG inhibited the EGF-induced phosphorylation of EGFR at Y992 and AKT at S473 in CC cells. Further, we showed that EGCG is capable of inhibiting the proliferation in 2D and elevating apoptosis in 2D and 3D spheroid culture via increased ROS generation and decreasing SOD enzymatic activity in both HPV positive ME180 and HPV negative C33A cells under basal and EGF-stimulated conditions. The mRNA expression of SOD1/2 along with their enzymatic activity, tumor necrosis factor-α (TNF-α) and programmed death-ligand 1 (PD-L1) transcripts was found to be downregulated by EGCG. The increase in inflammatory markers such as interleukin 6 (IL-6), C reactive protein (CRP) and TNF-α were elevated upon EGF treatment. The critical contributing molecules produced by CC cells that are reported to engage immune cells such as CD46, CD55 and CD59 levels are downregulated by EGCG. Pre-treatment with EGCG blocked EGF-induced changes in CC cells. Collectively, these findings indicate the inflammatory role for EGF and attest the anti-inflammatory potential of EGCG in CC cells.

Topical vaginal drug therapy in cervical cancer management: a review of clinical trials and preclinical evidence

Cervical cancer, the fourth most prevalent malignancy among women globally, is predominantly caused by persistent infection with high-risk human papillomavirus (HPV). Traditional methods such as surgery and chemotherapy are often associated with high incidence of adverse effects and may impact future pregnancies and childbirth especially for young female patient. Given that high-risk HPV primarily targets epithelial cells and cervical lesions are mainly localized in the cervix, local administration in the cervicovaginal area emerges as one of the most direct and effective methods for treating cervical cancer and its precursors. Topical vaginal administration not only minimizes systemic drug exposure but also simplifies application, reduces treatment costs, and supports fertility preservation. Nevertheless, there are currently no official recommendations for local therapies targeting HPV eradication or tumor lesion treatment. This review focuses on clinical trials and preclinical studies related to local pharmacotherapy for cervical tumors, with an emphasis on evaluating the efficacy of local treatments aimed at preventing the progression of cervical intraepithelial neoplasia. It encompasses therapeutic agents, clinical efficacy and adverse effects, treatment strategies, and innovations in formulations while also addressing the inherent challenges of vaginal administration and predicting future trends in this therapeutic field. Clinical studies have shown that trichloroacetic acid offers the best patient compliance and therapeutic response, although concerns remain regarding its uncontrolled depth of tissue penetration. In parallel, formulation optimization strategies such as prolonging vaginal residence time and employing nanotechnology to enhance drug loading and targeted delivery have shown promise in improving therapeutic outcomes.

Combinational therapy of cervical cancer consisting of probiotic particles and vincristine: a molecular in vitro study

Cervical cancer remains a major global health concern and ranks among the leading causes of cancer-related mortality in women. Although Vincristine Sulfate is a clinically established chemotherapeutic agent with potent anti-mitotic activity, its therapeutic utility is often restricted by dose-dependent toxicities and off-target effects. Recent evidence suggests that probiotics such as Lactobacillus fermentum may possess anti-tumor properties and could enhance the efficacy of conventional therapies. This study was designed to investigate whether co-administration of Lactobacillus fermentum could potentiate the anti-cancer effects of Vincristine Sulfate in HeLa cervical cancer cells, potentially allowing for a reduction in the effective chemotherapeutic dose. Lactobacillus fermentum was isolated from traditional dairy products and identified via molecular techniques. HeLa cells were treated with L. fermentum, Vincristine Sulfate, or a combination of both. Cell viability was assessed using the MTT assay, while apoptosis was quantified through Annexin V-FITC/PI staining and flow cytometry. Quantitative real-time PCR was employed to evaluate the expression of genes involved in apoptosis and the PI3K/AKT/mTOR signaling pathway. To evaluate the safety of bacterial treatment, L. fermentum was also tested on normal human umbilical vein endothelial cells (HUVECs) using the MTT assay. The half-maximal inhibitory concentrations (IC

Effects of royal jelly on ovary cancer cells proliferation and apoptosis

Abstract The aim of the present study is to investigate the proliferative or apoptotic effects of different doses and durations of Royal jelly (RJ) on serous type epithelial ovarian cancer, which is the most common epithelial ovarian cancer. For this purpose, cells of the Skov-3 human ovarian adenocarcinoma cell line were grown in McCoy medium and seeded in 6-well plates. RJ was prepared as a stock solution (1000 mg RJ/10 ml dH2O) and 1, 5, 10, 20, and 50 mg/ml RJ doses from the prepared stock solution were added to the medium for 24, 48, and 72 h incubated. After the treatment of RJ, the cell viability test (Tripan Blue), Ki-67 to determine the proliferative effect, cleaved-Caspase-3 and cleaved PARP expressions to determine its apoptotic effect were examined by immunocytochemical and immunofluorescence methods. In addition, findings were supported by the TUNEL method. As a result of the experiments, it was determined that 1 mg/ml and 24 h treatment of RJ did not affect cell proliferation and apoptosis, but generally, 50 mg/ml of RJ for 72 h inhibited proliferation in cancer cells and induced apoptosis. The use of royal jelly both monotherapeutically and in combination as an alternative treatment for ovarian cancer may provide the basis for new experimental protocols.

Characterization of lncRNAs contributing to drug resistance in epithelial ovarian cancer

Abstract Epithelial ovarian cancer (EOC) is the second leading cause of death among women with gynecological cancers, particularly in high-income countries. Despite significant advancements in molecular oncology and an initially positive response to primary chemotherapy, the development of drug resistance remains a major challenge in the effective management of EOC. Consequently, there is an urgent need for innovative biological markers that can enable early diagnosis and provide more accurate predictions of recurrence risk in ovarian cancer patients. This study investigated the expression profiles of seven specific long noncoding RNAs (lncRNAs)—SNHG7, TUG1, XIST1, PRLB, TLR8-AS1, ZFAS1, and PVT1—associated with epithelial ovarian cancer and their relationship with drug resistance. To achieve this, drug-resistant subtypes of aggressive EOC cell lines, including carboplatin/paclitaxel-resistant OVCAR3 and SKOV3 lines, were developed. The expression profiles of the selected lncRNAs were quantitatively analyzed using RT-qPCR across various ovarian cancer cell lines and in serum samples from 25 patients before chemotherapy, six months after treatment, and 23 healthy controls. The findings revealed that the target lncRNAs were significantly upregulated under drug-resistant conditions and in post-chemotherapy serum samples, suggesting their involvement in a complex regulatory network. These results highlight the critical roles of lncRNAs in the progression and treatment response of EOC, positioning them as potential therapeutic targets and biomarkers for early diagnosis and treatment stratification. Identifying reliable lncRNA biomarkers could enable the early detection of patients at risk for developing drug resistance, thereby facilitating personalized treatment strategies to improve patient outcomes and survival rates.

Targeting the TGF-β-p21 axis: a critical regulator of bleomycin–induced cell cycle arrest and apoptosis in vitro-implication for progressive cervical cancer therapy

Cervical cancer signifies a global health concern and is a major cause of cancer mortality in women worldwide. Dysregulation of apoptotic pathway and cell cycle play a role in cancer development. Aberrant signalling pathways leads to complex mechanisms leading to the severity. Bleomycin is an anti-tumor glycopeptide molecule which exhibits impressive cytotoxicity in cancer cells. However, its modulating significance on TGF-β induced cell cycle arrest and apoptosis in cervical cancer remains elusive. We confirmed the cytotoxicity, anti proliferative effect of bleomycin in HeLa cells. Meanwhile, bleomycin also led to the suppression of cell migration, invasion. Relative gene expression quantification for cell cycle regulatory, apoptotic, and TGF-β member's genes was done by qRT-PCR. Bleomycin markedly downregulated the expression of cyclin A2, cyclin B1 and cell cycle arrest at G

PARP1 acetylation at K119 is essential in regulating the progression and proliferation of cervical cancer cells

Cervical cancer, CC, is one of the malignant cancers in women worldwide. Many studies about the genesis and progression of CC have been done at genomic, transcriptional, translational, and epigenetic levels. However, much less is done at post-translational modification (PTM) level. We first used pan-PTM antibodies to compare the pan PTM levels between clinical normal cervical tissues and CC tissues; we then sent the selected samples for label-free identification of acetylation sites. Next, we employed WT or K119A mutant PARP1-EGFP-STREPII plasmid transfection in Hela cells and examined various indexes including colony formation, wound healing, ROS generation, early apoptosis, and immunofluorescence and quantification of proliferation markers (Ki67, PCNA, and p-P53). Last, we examined the levels of multiple important kinases regulating cervical cancer progression. We found that pan-acetylation was the most downregulated in clinical CC samples, whereas the acetylation of PARP1, Poly(ADP-ribose) polymerase-1, was upregulated at K119. Next, we showed that PARP1-WT overexpression significantly suppressed the proliferation and progression in CC cell line Hela, while K119A overexpression didn't show any impact. Finally, PARP1-WT overexpression significantly decreased p-ERK1/2 while didn't affect the phosphorylation levels of other important kinases such as AKT, MTOR, and RPS6. This study discovered a new type of PTM of PARP1 in CC, and showed that PARP1 acetylation at K119 is essential in regulating the proliferation and progression of CC through ERK1/2. Further studies are required to investigate how PARP1 acetylation impact its function.

IRTKS contributes to the malignant progression of cervical cancer cells

Cervical cancer (CC), one of the most aggressive tumors in women, has high risk rates of recurrence and metastasis. It is essential to study the key genes and proteins involved in CC development. IRTKS, a member of the IRSp53 family, has been reported as a tumor promoter in gastric and breast cancers. However, the biological role of IRTKS in CC is still unclear. The purpose of this study was to explore the biological function of IRTKS in CC cells in vitro and the effect of IRTKS on tumorigenesis in vivo. Siha and Hela cells were treated with si-RNA and plasmids. Cell proliferation and growth were detected by CCK8, colony formation assay and nude mouse tumorigenicity assay, respectively. Transwell assay was used to analyze cell migration and invasion. The expression of epithelial-mesenchymal transition (EMT)-related proteins was determined by western blot. IRTKS was highly expressed in CC. IRTKS contributed to the proliferation of CC cells in vitro and in vivo. Furthermore, IRTKS facilitated the migration and invasion of CC cells and modulated EMT. IRTKS plays a crucial role in CC tumorigenesis, suggesting it may be a potential key gene for new therapeutic strategies in CC.

Plumbagin as a preferential lead molecule to combat EGFR-driven matrix abundance and migration of cervical carcinoma cells

The handshake between the complex networks of matrix components in the tumor micro-environment (TME) is considered as a crucial event in the progression of several cancers including cervical carcinoma (CC). A number of studies report a connection between epidermal growth factor (EGF) and matrix component production. Studies demonstrate that the mechano-transduction trigger by collagen, influences the tumor cells to undergo epithelial-mesenchymal transition (EMT) and block the entry of drugs. We hypothesize that the intervention to prevent EGF triggered deposition of matrix components could sensitize several therapies for CC cells. We utilized morphological assessment, MTT assay, mitored tracking, acridine orange (AO)/ ethidium bromide (EtBr) staining and bromodeoxyuridine (BrdU) assay to measure the cell viability, mitochondrial activity, cellular apoptosis, and DNA synthesis. Clonogenic assay and scratch healing assay were executed to address the stemness and migratory potential. Detection of glycosaminoglycan's (GAGs), collagen, matrix metalloproteinase (MMP)-2/9 secretion and calcium (Ca

Clinical application of liquid biopsy in endometrial carcinoma

AbstractEndometrial cancer is the most common gynecological malignant tumor in women, and its morbidity and mortality have been rising in recent years. Over the past two decades, the diagnosis, prognosis, and therapeutic strategies for endometrial cancer have not significantly improved, and reliable biomarkers for detecting and monitoring EC recurrence and progression remain limited. Tumor genome analysis identified molecular alterations related to the growth and progression of endometrial cancer, but these data are incomplete. Recently, through extensive exploration of liquid biopsy, it has been determined that circulating tumor cells and circulating tumor DNA can lay a foundation for real-time and non-invasive monitoring of tumors and provide novel insights into cancer evolution, invasion, and metastasis. Hence, this review aimed to analyze the value of liquid biopsy in endometrial cancer screening, early diagnosis, treatment response, and prognosis monitoring in order to prolong the survival time of EC patients.

Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer

AbstractEndometrial cancer (EC) is the fifth most common cancer in women from developed countries, accounting for 4.8% of new cases and 2.1% of deaths. The genetic basis for the familial risk of endometrial cancer has not been completely defined. Mostly, hereditary EC is part of two syndromes as Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer syndrome (HBOC). LS is the prototypical hereditary cancer syndrome in EC and accounts for 2–6% of all endometrial cancers. This disease is caused by autosomal dominant mutations in DNA mismatch repair (MMR) genes. Patients carrying a germline mutation in one of the MMR genes have a cumulative lifetime risk to develop EC of 20–70%. HBOC is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers, but it can be also associated with other malignancies. HBOC results from germline mutations in BRCA1/2 genes. The aim of this study was to determine the mutational status of a cohort of 40 EC patients, 19 belonging to families with LS and 21 to HBOC. Mutation analysis of MLH1, MSH2, BRCA1 and BRCA2 genes showed pathogenic variants in 17/40 (42.5%) patients. Out of 19 patients belonging to LS families, 8 (42.1%) showed a pathogenic variant. Out of 21 patients belonging to HBOC families, 9 (42.8%) showed a pathogenic variant. 1/21 (4.8%) patient report 1 variant of unknown significance (UV), c.599 C > T (p.T200I), in BRCA2. Moreover, in 1/21 (4.8%) patient we identified a novel missense variant in BRCA2, c.9541A > T (p.Met3181Leu). Mutational analysis was extended to family members, both healthy and cancer affected, of mutated patients; all the tested relatives affected with cancer displayed the pathogenic variant. Our data suggest that patients with hereditary EC have a high percentage of mutations in the LS and HBOC main susceptibility genes; therefore, the surveillance for EC, already indicated in LS patients, should also be recommended for patients with HBOC.

Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy

Therapy-related acute leukemias (t-ALs) represent approximately 10-20% of all acute leukemias, are frequently resistant to chemotherapy, and are associated with guarded outcomes. The national comprehensive cancer network data suggest that t-AL cases are diagnosed at increasing rates in breast cancer patients treated with chemotherapeutic agents targeting topoisomerase II. Two cases of BRCA1-mutated ovarian and breast carcinoma who developed therapy-related APL and ALL, respectively, following topoisomerase II-directed therapy were characterized. Genomic characterization of therapy-related acute promyelocytic leukemia (t-APL) revealed a unique RARA intron 2 breakpoint (Chr17: 40347487) at 3'-end of RARA corroborating breakpoint clustering in t-APL following topoisomerase II inhibition. Both cases of this series harbored germline BRCA1 mutations. The germline BRCA1 mutation in patient with t-APL was detected in exon 8 (HGVS nucleotide: c.512dupT). This mutation in t-APL is extremely rare. Interestingly, t-ALL patient in this series had a BRCA1 mutation (HGVS nucleotide: c.68_69delAG; BIC designation: 187delAG) identical to a previously reported case after the treatment of same primary disease. It is unlikely that two breast cancer patients with identical BRCA1 mutation receiving topoisomerase II-targeted agents for the primary disease developed t-AL by chance. This report highlights the development of t-AL in BRAC1-mutated hereditary breast and ovarian cancer patients and warrants further studies on functional consequences of topoisomerase inhibition in this setting.

Investigation of molecular mechanisms underlying JAK/STAT signaling pathway in HPV-induced cervical carcinogenesis using ‘omics’ approach

The precise mechanism of action of Janus Kinases (JAK)/Signal Transducer and activator of Transcription (STAT) signaling in human papillomavirus (HPV)-associated cervical cancer (CaCx) is poorly defined. The present study dissected the underlying components of JAK/STAT signaling in HPV-positive cervical neoplasms. Whole transcriptome profile of CaCx cohort from TCGA database revealed elevated STAT3 and its impact on CaCx patients' survival. Using the RT

Therapeutic potential of microbiome modulation in reproductive cancers

The human microbiome, a complex ecosystem of microbial communities, plays a crucial role in physiological processes, and emerging research indicates a potential link between it and reproductive cancers. This connection highlights the significance of understanding the microbiome's influence on cancer development and treatment. A comprehensive review of current literature was conducted, focusing on studies that investigate the relationship between microbiome composition, reproductive cancer progression, and potential therapeutic approaches to modulate the microbiome. Evidence suggests that imbalances in the microbiome, known as dysbiosis, may contribute to the development and progression of reproductive cancers. Specific microbial populations have been associated with inflammatory responses, immune modulation, and even resistance to conventional therapies. Interventions such as probiotics, dietary modifications, and fecal microbiota transplantation have shown promise in restoring healthy microbiome function and improving cancer outcomes in pre-clinical models, with pilot studies in humans indicating potential benefits. This review explores the therapeutic potential of microbiome modulation in the management of reproductive cancers, discussing the mechanisms involved and the evidence supporting microbiome-targeted therapies. Future research is warranted to unravel the complex interactions between the microbiome and reproductive cancer pathophysiology, paving the way for innovative approaches.

Unraveling the role of EPHA2 in regulating migration and immunomodulation processes in cervical cancer: exploring the synergic effect of 17β-estradiol on cancer progression

Cervical cancer remained among the most prevalent cancers in women. Erythropoietin-producing hepatocellular A2 (EPHA2) is overexpressed in many cancers, including cervical cancer, and the mechanism by which it regulates cervical cancer progression is not yet fully understood. Exosomes are extracellular vesicles that carry information in the form of biomolecules, deliver it to the recipient cell, and play a vital role in cellular communication. 17β-Estradiol is the natural female steroid hormone with the greatest estrogenic activity, and it induces cell death in cancer. In this study, we investigated the function of EPHA2 in cervical cancer migration and immunomodulation and the presence of EPHA2 in the cervical cancer serum-derived exosome. A knockdown of EPHA2 (KD-EPHA2) in cervical cancer reduces cancer cell migration by regulating the CD113/Ezrin pathway. Furthermore, EPHA2 exhibited significant involvement in immunomodulation by orchestrating IL-6-mediated signalling cascades, including the AKT-mTOR and JAK-STAT pathways. Immune infiltration analysis revealed a correlation between EPHA2 expression in cervical cancer and the infiltration of various immune cell populations. KD-EPHA2 enhances the 17β-Estradiol inhibitory effect on cell proliferation and migration during cancer progression. In summary, our study revealed that EPHA2 is overexpressed in cervical cancer and plays a vital role in cancer cell migration and immunomodulation, and 17β-Estradiol, along with KD-EPHA2, enhances the inhibitory effect on cancer cell migration and proliferation.

Modulation of the tumor microenvironment in non-muscle-invasive bladder cancer by OncoTherad® (MRB-CFI-1) nanoimmunotherapy: effects on tumor-associated macrophages, tumor-infiltrating lymphocytes, and monoamine oxidases

Bit1 promotes the progression of gastric cancer by facilitating epithelial–mesenchymal transition and alleviating apoptosis

Scutellarin triggers ferroptosis in ovarian cancer cells via inhibiting AKT/mTOR and JAK2/STAT3 pathways

Ovarian cancer (OC) ranks as the second most prevalent gynecologic malignancy worldwide, largely attributed to the difficulties in detecting early stages, frequent disease reappearance, and unresponsiveness to existing therapies. Contemporary treatment selections for individuals with OC remain limited. Scutellarin (Scu), an active compound, demonstrates suppressive properties against multiplication, invasion, and survival of certain cancer cell types. Nevertheless, the exact anti-cancer properties and molecular pathways of Scu in OC are still not fully understood. This investigation sought to examine the therapeutic impact of Scu and its potential mechanisms in OC. A series of assays, encompassing cell counting kit-8 (CCK-8), colony-formation assay, EdU staining, scratch/wound healing assay, matrigel invasion assay, DHE staining, flow cytometry, Western blotting, ferrous ion content assay kit, and immunofluorescence staining were employed to investigate the role and mechanisms of Scu in OC cell lines (SKOV3 and HO-8910). Scu markedly diminished cell viability, proliferation, and colony formation in both SKOV3 and HO-8910 cells. Scu substantially inhibited OC cells' migration, invasion, and epithelial-mesenchymal transition (EMT). Additionally, the flow cytometry data and Western blot results of Bax and Bcl-2 protein levels indicated that Scu induced cell apoptosis in both SKOV3 and HO-8910 cells. Furthermore, Scu induced cell ferroptosis by upregulating the levels of reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE), and Fe2+ while downregulating the expression of specificity protein 1 (SP1), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). The anti-cancer capabilities of Scu were also linked to the inhibition of the phosphorylated forms of AKT, mTOR, JAK2, and STAT3. Lastly, cell apoptosis and ferroptosis induced by Scu were counteracted by AKT agonist SC79. The findings demonstrate that Scu effectively inhibited cell multiplication, migration, invasion, and EMT, while inducing oxidative stress, apoptosis, and ferroptosis in SKOV3 and HO-8910 cells. These effects were likely mediated by inhibiting the AKT/mTOR and JAK2/STAT3 signaling cascades. This investigation suggests that Scu holds potential as a promising chemotherapeutic agent for treating OC.

Pterostilbene as a Multifaceted Anticancer Agent: Molecular Mechanisms, Therapeutic Potential and Future Directions

Comprehensive analysis of VDAC1 in gynecological tumors and structure-based virtual screening of its natural inhibitors

Drug repurposing in oncology: a path beyond the bottleneck

Polyphyllin I inhibits ovarian cancer growth by inducing G0/G1 phase arrest and inhibiting the c-Myc signaling pathway

Kinesin superfamily proteins in ovarian cancer: from molecular mechanisms to clinical applications

Ovarian cancer remains one of the most lethal malignancies affecting women, largely due to its asymptomatic onset and frequent diagnosis at advanced stages. Emerging evidence has underscored the pivotal role of kinesin superfamily proteins (KIFs) in orchestrating the cellular mechanisms underlying tumor initiation and progression, particularly in ovarian cancer. These microtubule-associated motor proteins are essential for intracellular transport, cell division, signal transduction, and organelle positioning. Dysregulation of KIFs has been implicated in enhanced cellular proliferation, metastasis, and resistance to chemotherapy. In ovarian cancer, specific KIF members have been shown to promote cell motility and interfere with key signaling pathways, thereby accelerating tumor progression. Elevated expression levels of certain KIFs correlate with poor patient prognosis and reduced overall survival. This review consolidates current insights into the role of KIFs in ovarian cancer pathogenesis and emphasizes their potential as therapeutic targets. Elucidating the mechanistic involvement of KIFs in this malignancy may pave the way for innovative diagnostic, prognostic, and therapeutic strategies aimed at improving clinical outcomes in this highly aggressive cancer type.

Multifaceted role of erlotinib in various cancer: nanotechnology intervention, patent landscape, and advancements in clinical trials

Targeting TGF-β: a promising strategy for cancer therapy

Ovarian cancer, neutrophil hitchhiking, and NETs: unraveling their role in pathogenesis and management

Ovarian cancer is the most lethal gynecologic malignancy, driven by extensive genetic heterogeneity, clonal evolution, and resistance to therapy. Despite advances in treatment, recurrence remains common, highlighting the urgent need for novel therapeutic strategies. Neutrophil extracellular traps (NETs)-web-like DNA-protein complexes released during NETosis-have recently emerged as key facilitators of tumor progression across multiple cancers. However, their role in ovarian cancer remains underexplored. NETs contribute to metastasis, angiogenesis, immune evasion, and chemoresistance, creating a pro-tumorigenic microenvironment. This review identifies critical knowledge gaps in NET-mediated mechanisms in ovarian cancer and introduces, for the first time in this context, the concept of neutrophil hitchhiking, whereby circulating tumor cells exploit neutrophils to enhance metastatic dissemination. We examine molecular pathways driving NETosis and their influence on the tumor microenvironment, highlighting how NET-targeted therapies-including NETosis inhibitors and immune modulators-offer promising avenues to suppress metastasis, restore immune surveillance, and improve treatment outcomes. By illuminating this underexplored axis of neutrophil-tumor interaction, we aim to stimulate research and therapeutic development that could transform ovarian cancer management.

Hormones as a double-edged sword: the role of hormones in cancer progression and the potential of targeted hormone therapies

The anti-ovarian carcinoma activity of l-amino acid oxidase from Crotalus adamanteus venom in vivo and in vitro

Snake venom L-Amino-acid oxidase (svLAAO) has become a critical research target in molecular biology and medical science since its widespread presence and diverse biological roles, including antitumor application. Our research confirmed that Crotalus adamanteus (C. adamanteus) venom LAAO exhibited potential anti-ovarian cancer activity both in vivo and in vitro. C. adamanteus venom LAAO significantly reduced viability of ovarian cancer cells and caused morphological changes that preceded cell death. The results of molecular biology experiments showed that C. adamanteus venom LAAO caused expression changes of genes related to apoptotic pathways either intrinsically or extrinsically in ovarian cancer cells. Animal experiments and histological analysis also proved that C. adamanteus venom LAAO could effectively inhibit the tissue damage caused by ovarian cancer, and animals treated with C. adamanteus venom LAAO showed higher survival time. Catalase blocked the major apoptosis induction of C. adamanteus venom LAAO on ovarian cancer cells, suggesting that the cytotoxicity of C. adamanteus venom LAAO on ovarian cancer cells was mainly mediated by H

STXBP6 regulates growth, metastasis and lipid metabolism of ovarian cancer cells via the PI3K/AKT signaling pathway

Ovarian cancer (OC) is the primary cause of mortality related to cancers of the female reproductive system. Early diagnosis remains a major challenge, contributing to a high mortality rate and underscoring an urgent need for novel diagnostic approaches and effective therapeutic strategies. Here, we identify Syntaxin binding protein 6 (STXBP6) as a previously unrecognized oncogenic driver in OC. We demonstrate that STXBP6 expression is markedly elevated in OC tissues and cells and that it promotes OC growth and metastasis both in vitro and in vivo. RNA sequencing revealed that STXBP6 reprograms lipid metabolism, and mechanistic studies confirmed that it enhances OC progression through fatty acid oxidation (FAO). Moreover, activation of the PI3K/AKT signaling pathway was essential for STXBP6-driven FAO and malignant phenotypes. These findings uncover a novel STXBP6/PI3K/AKT axis, providing new insights into OC metabolic reprogramming and potential therapeutic targets.

Targeted drug delivery in cervical carcinoma: the role of gold nanoparticles in enhancing treatment efficacy

As the fourth most common cancer affecting women globally, cervical cancer presents a significant health challenge. Nanotechnology offers a promising new frontier for treatment, with gold nanoparticles (AuNPs) emerging as a powerful tool for enhancing therapeutic effectiveness.This review focuses on the synthesis of AuNPs and their strategic application in targeted drug delivery systems to combat cervical cancer. Gold nanoparticles are exceptionally well suited for this role due to a unique combination of properties, including their small size, high surface-area-to-volume ratio, excellent stability, and biocompatibility. These traits make them ideal vehicles for medical use.Beyond targeted drug delivery, AuNPs can also act as radiosensitizers, increasing the susceptibility of cancer cells to radiation. This synergy has the potential to make radiation therapy more precise and effective, highlighting the multifaceted role of gold nanoparticles in developing more advanced and targeted treatments for cervical cancer.

LncRNA LOXL1-AS1 promotes ovarian cancer progression by enhanced BRIP1 mRNA stability

Long non-coding RNAs (lncRNAs) have crucial effects on the development of malignant tumors. This work focused on determining how LOXL1-AS1 contributed to epithelial ovarian cancer development. As indicated by quantitative RT-polymerase chain reaction (qRT-PCR), LOXL1-AS1 showed significant overexpression within ovarian epithelial cancer tissues and ovarian cancer cells compared with non-cancer samples and regular human epithelial cell lines. According to CCK-8, flow cytometry, plate cloning, cell scratch test, a series of cell function tests in vitro, a nude mouse transplanted tumor model, and Western blot assays, LOXL1-AS1 siRNA transfection suppressed the growth, invasion, and epithelial-to-mesenchymal transformation characteristics of SKOV3 and A2780 cells in vitro and vivo. As discovered, LOXL1-AS1 targets BRCA1-interacting protein C-terminal helicase 1 (BRIP1) mRNA, resulting in a malignant phenotype of ovarian cancer. Overexpression of BRIP1 reversed the inhibition of cell progression induced by LOXL1-AS1 siRNA. In addition, based on RNA stability experiments, LOXL1-AS1 enhanced ovarian cancer cell growth and metastasis by stabilizing BRIP1 mRNA. Our findings reveal a novel mechanism of how LOXL1-AS1 enhances epithelial ovarian cancer progression by specifically regulating BRIP1 mRNA stability. This provides the potential therapeutic application of LOXL1-AS1 targeting BRIP1 for treating ovarian cancer.

Detecting vascular normalization in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is highly angiogenic, making this tumor attractive, in the last 20 years, for analysis of clinical and biological functions of the VEGF family, relating altered expression with patient's clinical responses. Currently, analyzes and validations have yet to be made to relate vascular normalization with combinations of immune-, chemo- or radiotherapy. We review the main clinical analyses capable of identifying markers of vascular normalization including functional biomarkers (e.g., perfusion parameters by imaging techniques), molecular biomarkers (e.g., circulating protein levels and cfDNA), blood biomarkers, physiological markers and other approaches. Many markers cited here have not yet been analyzed in EOC but have shown promising results in tumors such as pancreatic and glioblastoma cancer, which share similarities with ovarian cancer. The methodologies presented have the advantage of not being invasive and immediately detecting vascular normalization, mainly using imaging techniques.

Effects of PELP1 on proliferation, metastasis and angiogenesis of epithelial ovarian cancer

To investigate the effects of Proline-, Glutamic acid- and Leucine-rich protein 1(PELP1) on the biological behaviors of epithelial ovarian cancer (EOC) cells and its role in promoting angiogenesis through the regulation of VEGFA expression and secretion. Bioinformatics analysis was performed to evaluate the correlation between PELP1 and VEGFA. The expression levels and subcellular localization of PELP1 and VEGFA in EOC cell lines were assessed using Western blot (WB), quantitative real-time PCR (qRT-PCR) and immunofluorescence. Functional assays, including EdU proliferation assays, wound healing assays, Transwell invasion assays and WB were conducted to examine the effects of PELP1 overexpression. Conditioned medium (CM) from PELP1-overexpression cells was used to culture human umbilical vein endothelial cells (HUVECs) and angiogenesis was evaluated using Transwell migration, wound healing, and tube formation assays. VEGFA expression and secretion were analyzed by immunofluorescence, qRT-PCR, and enzyme-linked immunosorbent assays (ELISA). WB and ELISA were performed to validate the effects of the VEGFA inhibitor (HY-117661) on both the expression and secretion of VEGFA. Functional rescue experiments, including migration and tube formation assays, were conducted to verify whether PELP1 regulated angiogenesis through VEGFA. Bioinformatics analysis revealed a positive correlation between PELP1 and VEGFA. Both proteins were significantly upregulated in EOC cells compared to normal ovarian epithelial cells. Overexpression of PELP1 enhanced proliferation, migration, invasion and the expression of metastasis-associated proteins, including N-cadherin and Vimentin. Additionally, PELP1 upregulated VEGFA expression and secretion, which subsequently promoted HUVEC migration and angiogenesis. PELP1 promotes EOC progression by enhancing cellular proliferation, metastasis and angiogenesis through the regulation of VEGFA. These findings suggest that PELP1 could serve as a potential therapeutic target for EOC.

NEDD4 signaling: a new frontier in the diagnosis and treatment of breast and ovarian cancers

Currently, breast cancer (BC) and ovarian cancer (OC) are the most prevalent forms of cancer among women worldwide. Even though BC has a favorable outlook when detected early and managed appropriately compared to OC, the spread of BC and OC to other parts of the body, known as metastasis, is a significant cause of death. A robust association exists between genetic and protein alterations and post-translational modifications (PTMs), significantly impacting tumor formation, advancement, and prognosis. Ubiquitination, a crucial PTM, regulates almost all aspects of cellular function, and E3-ligase-mediated ubiquitination is a pivotal process that controls the speed of the protein ubiquitination cascade. NEDD4-1, a neural developmentally downregulated protein 4-1, is a crucial E3 ligase that plays a significant role in regulating several proteins that have important functions in the development and progression of BC and OC, thus controlling BC and OC cells' movement, infiltration, and multiplication. This review discusses the latest developments in comprehending NEDD4-1 substrates and their involvement in signal transduction pathways in BC and OC. NEDD4-1 likely serves as a novel diagnostic indicator and a target for therapy in the battle against both cancers.

Curcumin-gold nanoshell mediated near-infrared irradiation on human ovarian cancer cell: in vitro study

Ovarian cancer is considered a predominant female reproductive malignancy and poses a significant threat due to its 80-90% fatality rate. The typical approach involves surgery and chemotherapy, which due to problems such as drug resistance, encourage researchers to use new methods such as nanotechnology. The current study introduces a novel strategy: leveraging Curcumin-Gold Nanoshells (Cur-AuNShs) to combat chemotherapy's adverse effects and overcome drug resistance through hyperthermia mediation. Gold-based nanoparticles that absorb laser have shown the potential to target and treat cancer selectively through highly efficient light-to-heat conversion. This experimental study focused on the synthesis of AuNShs and their subsequent conjugation with Cur. The gold shell coverage on the surfaces of silica nanoparticles was examined using UV-VIS spectroscopy and transmission electron microscopy (TEM). Dynamic light scattering (DLS) and Zeta potential analysis were employed to evaluate the stability of particle size and surface charge. Human ovarian carcinoma cell lines (SKOV-3) were treated with a combination of Cur (15 μM) and AuNShs (75 μM), under the activation of near-infrared (NIR) laser irradiation at a power of 2.5 W/cm

RETRACTED ARTICLE: Alternative use of droxidopa for treating cervical cancer: inhibiting transferase, cell cycle signalling, and transport proteins via multitarget docking, DFT, MD simulations, and binding free energy studies

Cervical cancer develops due to the uncontrolled growth of abnormal cells in the cervix, mainly triggered by a persistent infection with high-risk types of human papillomavirus (HPV), a sexually transmitted virus. Factors that increase the risk include having multiple sexual partners, engaging in sexual activity at an early age, smoking, and a compromised immune system. Globally, it ranks as the fourth most prevalent cancer among women, with over 600000 new cases and 340000 deaths each year. The disease disproportionately impacts women in low- and middle-income countries, where access to screening and vaccination is often limited. Drug resistance emerges when cancer cells evade treatment through genetic mutations, altered targets, and efflux pump overexpression. Multitargeted docking identifies compounds interacting with multiple targets where a drug can inhibit crucial pathways, improving efficacy and reducing resistance chances. In this study, we examined Transferase, Cell Cycle Signalling, and Transport Proteins associated with PDB IDs 2WVI, 2B9R, 3VHX, and 3KND. These targets were subjected to multitargeted docking using an FDA-approved drug library. Droxidopa was identified as a multitargeted drug, with docking scores ranging from - 5.99 to - 11.37 kcal/mol and MM/GBSA scores between - 20.13 and - 43.00 kcal/mol. The interaction fingerprints identified the most interacted residues with counts are 4GLN, 4GLU, 3ARG, and 3TRP, and the Pharmacokinetics and DFT analysis favoured the compound's suitability. Furthermore, 5 ns (nanoseconds) WaterMap for hydration sites and 100 ns MD simulation in NPT ensemble at 330 K temperature have resulted in acceptable deviations, fluctuations, and many intermolecular interactions, and binding free energy computations have favoured droxidopa's use against cervical cancer-however, experimental studies are needed before its use including the in-vitro and in-vivo studies.

Ovarian cancer and its management through advanced drug delivery system

Ovarian cancer is the deadliest gynecological cancer, often being diagnosed at a late-stage when the disease is already advanced. This makes it known as the ''silent killer'' due to its high mortality rate among women. The ovary itself is composed of three main types of cells epithelial cells, germ cells, and stromal cells. Over 90% of all occurrences of ovarian cancer are epithelial ovarian carcinoma. Ovarian cancer is responsible for 2.5% of cancer in women. The primary signs include stomach bloating, trouble eating or feeling full rapidly, fatigue, and discomfort during intercourse. The management of ovarian cancer is improved by advanced drug delivery systems because they increase therapeutic targeting, reduce side effects, and overcome drug resistance. Accurate distribution to cancer cells is made possible by methods such as ligand-functionalized nanomedicines, dual-targeted nano-drugs, drug conjugates, antibody-drug conjugates and peptide/folate drug conjugates. These technologies enhance individualized and successful ovarian cancer treatment outcomes by maximizing chemotherapy efficacy, extending drug release, and lowering toxicity.

Study of the effect of zinc oxide, selenium, and silver nanoparticles on the expression level of oxidative stress-associated genes in ovarian cancer

Reactive oxygen species (ROS) generated by oxidative stress have emerged as critical factors in the pathophysiology of malignancies. This study investigated the antioxidant and anticancer properties of zinc (Zn), selenium (Se), and silver (Ag) nanoparticles (NPs) against the A2780 human ovarian cancer cell line. Here, the bioinformatics approach was used to determine the top differentially expressed genes associated with oxidative stress. The ZnO-, Se-, and Ag-NPs were then synthesized via a green synthesis method and subsequently characterized using techniques, such as FTIR, XRD, DLS, zeta potential analysis, FESEM, and TEM. The antioxidant capacity of the NPs was evaluated using a DPPH scavenging assay and their effect on superoxide dismutase enzyme activity was determined. HDF and A2780 cells were treated with varying concentrations of ZnO-, Se-, and Ag-NPs, and cell viability and colony formation were assessed using MTT and clonogenic assays, respectively. Additionally, qPCR was performed to analyze the expression of the candidate genes NOX4, SOD2, and NR4A4. Characterization techniques confirmed the successful synthesis of pure, crystalline, and spherical NPs. Antioxidant assays demonstrated the significant antioxidant properties of ZnO-, Se-, and Ag-NPs. In vitro studies indicated that ZnO-, Se-, and Ag-NPs effectively inhibited cell proliferation and suppressed colony formation, likely owing to the downregulation of NOX4 and upregulation of SOD2 genes. Our findings suggest that ZnO-, Se-, and Ag-NPs may serve as promising anticancer agents for ovarian cancer and NOX4 downregulation and SOD2 upregulation can be proposed as oxidative stress biomarkers; however, further experimental investigation is required to elucidate the therapeutic potential of NPs and the early detection potential of biomarkers.

Unveiling the potency of FDA-approved oxidopamine HBr for cervical cancer regulation and replication proteins

Cervical Cancer remains a women's health concern worldwide and ranks among the most prevalent cancers, particularly in developing countries. Many women are diagnosed with cervical cancer, with a substantial number succumbing to the disease even after the availability of vaccines and drugs. The tumour microenvironment often exhibits immune evasion, including suppression of T-cell activity and altered cytokine, impacting the efficacy of therapeutic interventions and highlighting the need for treatments to modulate the immune response. Despite efforts to promote HPV vaccination and regular screenings, it causes many deaths, underscoring the urgent need for continued research, healthcare access, and rapid drug development or repurposing. In this study, we identified various proteins involved in cervical cancer cell cycle regulation and DNA replication proteins, performed the multitargeted docking with an FDA-approved library, and identified Oxidopamine HBr as a multitargeted drug. Studies extended with pharmacokinetics and compared with the standard values followed by DFT, which supported the compound as a multitargeted inhibitor. Further, the docked complexes were taken for the interaction fingerprints, and it was identified that there are many 9 polar, 5 hydrophobic, 2 aromatic, and 2 basic residues. We extended our studies for 100ns MD Simulation in water, and the computations explored the deviation and fluctuations under 2Å and many intermolecular interactions; the same trajectory files were used for the MM\GBSA studies. All the studies have supported the Oxidopamine HBr as a cervical cancer multitargeted inhibitor-however, experimental studies are needed before human use.

The emerging role of breast cancer derived extracellular vesicles-mediated intercellular communication in ovarian cancer progression and metastasis

Breast cancer is one of the most occurring cancer types in women worldwide and metastasizes to several organs such as bone, lungs, liver, brain, and ovaries. Extracellular vesicles (EVs) mediate intercellular signaling which has a profound effect on tumor development and metastasis. Recent developments in the field of EVs provide an opportunity to investigate the roles of EVs released from tumor cells in metastasis. In this study, we compared the effects of metastatic breast cancer-derived EVs on both nonluteinized granulosa HGrC1 and ovarian cancer OVCAR-3 cells in terms of proliferation, invasion, apoptosis, and gene expression levels. EVs were isolated from the culture medium of metastatic breast cancer cell line MDA-MB-231 by ultracentrifugation. Cell proliferation, apoptosis, cell cycle, invasion, and cellular uptake analysis were performed to clarify the roles of tumor-derived EVs in both cells. 6.85 × 10

Cancer stemness kinase inhibitor amcasertib: a promising therapeutic agent in ovarian cancer stem and cancer cell models with different genetic profiles

Ovarian cancer, often referred to as the 'silent killer,' is a significant contributor to mortality rates. Emerging evidence implicates Nanog as a potential therapeutic target in ovarian cancer. Amcasertib (BBI-503) is an orally administered primary class stemness kinase inhibitor that effectively targets NANOG and various cancer stem cell pathways by specifically inhibiting serine-threonine stemness kinases. This study aimed to evaluate the antineoplastic effects of Nanog inhibition, a critical transcription factor associated with pluripotency and its role in ovarian cancer tumorigenesis, using the novel therapeutic agent Amcasertib in ovarian cancer cells characterized by distinct genetic profiles. The cytotoxicity of Amcasertib was assessed in both ovarian cancer and cancer stem cell models utilizing the Xelligence-RTCA system. The impact of the determined IC50 dose on apoptosis, invasion, migration, epithelial-mesenchymal transition (EMT), cell cycle progression, colony formation, and spheroid growth was evaluated using appropriate analytical techniques. Our findings revealed that Amcasertib exhibited significant antiproliferative effects and induced apoptosis in ovarian cancer and cancer stem cells. Moreover, Amcasertib caused G1 phase arrest and impeded colony formation in MDAH-2774 cells. Additionally, Amcasertib effectively inhibited spheroid growth in OVCAR-3 and OCSC cells. Notably, it demonstrated the ability to suppress invasion and migration in MDAH-2774 and OCSC cells. Furthermore, the suppression of Nanog-mediated stem cell-like features by Amcasertib was particularly pronounced in ER-negative ovarian cancer and cancer stem cells, highlighting its high anticancer efficacy in this subgroup. These results suggest that Amcasertib holds promise as a potential standalone or combination therapy agent for the treatment of ER-negative ovarian cancer.

Multitargeted inhibitory effect of Mitoxantrone 2HCl on cervical cancer cell cycle regulatory proteins: a multitargeted docking-based MM\GBSA and MD simulation study

Cervical cancer remains a significant global health concern that starts in the cervix, the lower part of the uterus that connects to the vagina and is caused by the human papillomavirus (HPV), necessitating the development of effective multitargeted effective and resistance-proof therapies. In early-stage cervical cancer may not show any symptoms, however, as the cancer progresses, some people may experience- abnormal vaginal bleeding, watery or bloody vaginal discharge, pain in the pelvis or lower back, pain during sex, and frequent and painful urination. In this study, we screened the complete FDA-approved drug library using a multitargeted inhibitory approach against four cervical cancer proteins, namely mitotic arrest deficient -2, DNA polymerase epsilon B-subunit, benzimidazole-related -1, and threonine-protein kinase-1 which crucially plays its role for the in its development process. We employed the HTVS, SP and XP algorithms for efficient filtering and screening that helped to identify Mitoxantrone 2HCl against all of them with docking and MM\GBSA scores ranging from - 11.63 to - 7.802 kcal/mol and - 74.38 to - 47.73 kcal/mol, respectively. We also evaluated the interaction patterns of each complex and the pharmacokinetics properties that helped gain insight into interactions. Subsequently, we performed multiscale MD simulations for 100 ns to understand the dynamic behaviour and stability of the Mitoxantrone 2HCl -protein complexes that revealed the formation of stable drug-protein complexes and provided insights into the molecular interactions that contribute to Mitoxantrone's inhibitory effects on these proteins and can be a better drug for cervical cancer. However, experimental studies of these findings could pave the way for therapies to combat cervical cancer effectively.

Niosomes nanoparticles as a novel approach in drug delivery enhances anticancer properties of chrysin in human ovarian carcinoma cells (SKOV3): an in vitro study

Chrysin (Chr) has drawn a lot of attention recently due to its possible anticancer properties. However, Chr's short half-life and low bioavailability restricted its utility as a medicinal agent. The purpose of this research is to design, synthesize, and test the cytotoxic effects of nano-niosomes containing chrysin (Chr-Nio) on the SKOV3 ovarian cancer cell line. Chr-Nio has a nanoparticle polydispersity index (PDI) of 0.156 and a zeta potential of - 27.4 mV, with an average diameter of 105 nm. Furthermore, Chr was encapsulated in Nio with an entrapment effectiveness of 85.5%. Chr-Nio cytotoxicity was shown to be more than free Chr in a time- and dose-dependent manner. Furthermore, as compared to free Chr-treated cells, the mRNA expression level of apoptotic genes Bcl-2, Bax, and caspase-3 in Chr-Nio-treated cells was considerably altered. According to the data, Chr may inhibit SKOV3 cell migration in vitro scratch wound experiments in a dose-dependent manner, and cells treated with Chr-Nio had the highest percentage of cell death. The findings of this study suggested that encapsulating Chr in niosome nanoparticles might be an effective medication delivery strategy for increasing Chr anticancer effects in the treatment of ovarian cancer.

Analyzing the impact of ATF3 in tumorigenesis and immune cell infiltration of ovarian tumor: a bioinformatics study

ATF3 is an essential transcription activator in regulating cancer-related genetic expression. To identify the role of ATF3 in ovarian tumor, we investigated the correlation between ATF3 expression and the clinicopathological properties using multiple database. The cBioPortal and GEPIA database displayed the clinical information of ovarian patients harboring or without harboring ATF3 mutation. Furthermore, we assessed the relationship between survival and ATF3 expression level using Kaplan-Meier plotter, which reveals that the ovarian patients with higher expression of ATF3 suffered the worse overall survival and progression-free survival. The differentially expressed genes were analyzed using gene ontology, protein-protein interaction network, and gene set enrichment analysis to identify the hub gene and critical pathways, significantly affecting the tumorigenesis of ovarian tumor. Finally, we assessed the correlation between ATF3 and immune cell infiltration using Tumor Immunoassay Resource (TIMER) database. The results demonstrated that higher expression has a positive correlation with macrophage infiltration, expression for M1- and M2-type macrophages. Our study suggests that ATF3 can regulate the cell cycle and heme-related oxidative phosphorylation process, and it may be a critical factor to regulate the macrophage cell to be infiltrated into ovarian cancer. ATF3 can be used as a biomarker for diagnosis and therapy of ovarian tumor.

Diosmetin induces apoptosis in ovarian cancer cells by activating reactive oxygen species and inhibiting the Nrf2 pathway

The fatality rate of ovarian cancer ranks first among gynecological tumors, and the prognosis is poor. Diosmetin (Dio), a natural flavonoid obtained from citrus fruits, has been shown to have anti-tumor effects in lung, liver, and skin cancers. We aimed to investigate the effects of Dio on ovarian cancer A2780 and SKOV3 cells along with the underlying mechanisms. Our data showed that Dio inhibited the proliferation, migration, and invasion of these cells and induced their apoptosis. Moreover, Dio upregulated the levels of Bax and cleaved Caspase-3 and PARP while downregulating the level of Bcl2. Mechanistically, our results revealed that Dio inhibited Nrf2 and induced the production of reactive oxygen species (ROS). The ROS scavenger N-acetyl-L-cysteine (NAC) suppressed the inhibitory effect of Dio on the proliferation of the ovarian cancer cells. Additionally, overexpression of Nrf2 partially suppressed the Dio-induced apoptosis and proliferation inhibition in these cells. These findings indicate that Dio exerts an anti-tumor activity by upregulating ROS levels and inhibiting Nrf2, indicating that Dio is a promising chemotherapeutic candidate for the treatment of ovarian cancer.

Investigation of cytotoxic and apoptotic effects of disodium pentaborate decahydrate on ovarian cancer cells and assessment of gene profiling

After revealing the anti-cancer properties of boron, which is included in the category of essential elements for human health by the World Health Organization, the therapeutic potential of boron compounds has been begun to be evaluated, and its molecular effect mechanisms have still been among the research subjects. In ovarian cancer, mutations or amplifications frequently occur in the PI3K/Akt/mTOR pathway components, and dysregulation of this pathway is shown among the causes of treatment failure. In the present study, it was aimed to investigate the anti-cancer properties of boron-containing DPD in SKOV3 cells, which is an epithelial ovarian cancer model, through PI3K/AKT/mTOR pathway. The cytotoxic activity of DPD in SKOV3 cells was evaluated by WST-1 test, apoptotic effect by Annexin V and JC-1 test. The gene expressions associated with PI3K/AKT/mTOR pathway were determined by real-time qRT-PCR. In SKOV3 cells, the IC

Homodimer 99mTc-HYNIC-E(SSSLTVPWY)2 peptide improved HER2-overexpressed tumor targeting and imaging

We hypothesized that a novel design of the LTVPWY (LY) peptide might exhibit a great potential for improving binding affinity and targeting HER2-overexpressed tumors. Hence, new dimer construction of

Phase II study of sodium valproate in combination with oral etoposide in platinum-resistant ovarian cancer

Patients with platinum-resistant ovarian cancer (PROC) have limited therapeutic options and poor survival. There is a need for the development of newer therapies. Sodium valproic acid (VPA) is a short-chain fatty acid histone deacetylase (HDAC) inhibitor with antitumor activity in preclinical models of PROC. Synergism with conventional cytotoxic agents like etoposide has been demonstrated. In this prospective, single-arm, open-label, phase 2 study, we included patients ≥ 18 years with histologically or cytologically confirmed PROC and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-3. Patients received oral VPA 60 mg/kg/day in three divided doses for 3 days (D1-D3), followed by oral etoposide 50 mg once daily for two consecutive weeks (D4-D17). Serum samples were collected to assess peak VPA drug levels. The primary endpoint was the overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. We sought to show an improvement in response rate from 25% (historically with oral etoposide) to 40% with the addition of VPA. 27 patients were enrolled in the study, and 18 [median age: 52 (45-59) years; serous histology:17 (94%); ECOG-PS 2 or 3: 14 (78%)] were evaluable for the response after 4 months. Nine patients were lost from follow-up before achieving the primary endpoint (mainly due to Covid-related lockdown issues). The median number of prior lines of treatment was 2 (1-3). ORR was 0% according to GCIG criteria. The disease was stable in two patients [clinical benefit rate (CBR) of 11%]. The median OS and PFS were 7 months and 2 months, respectively. Grade ≥ 3 adverse events were reported in 6 (33%) patients. The addition of valproic acid to oral etoposide in patients with PROC and poor general condition was not helpful and failed to improve responses compared to those historically achieved with single-agent etoposide. However, further phase 2 randomized controlled trials with larger sample size can be done to confirm the findings.

The challenge of selecting tumor antigens for chimeric antigen receptor T-cell therapy in ovarian cancer

Ovarian cancer (OC) is one of the most common cancers in women, with a high mortality rate and very few available and effective treatments. Evidence shows that immunotherapy in OC has not been very successful because immune checkpoint blockers have not achieved satisfactory clinical outcomes. On the other hand, as one of the effective treatment approaches, chimeric antigen receptor T-cell (CAR T-cell) therapy has gained a moral position, especially in blood malignancies. Although in solid tumors, CAR T-cell therapy faces various complications and challenges. One of these challenges is selecting the appropriate tumor antigen targeted by CAR T cells, making the selection difficult due to the expression of antigens by tumor cells and normal cells. In addition, the rate of tumor antigen expression and CAR T-cell access to the desired antigen and proper stimulation of CAR T cells can be other important points in antigen selection. This review summarized common tumor antigens and the challenges of selecting them in CAR T cells therapy of OC.

SND1 confers chemoresistance to cisplatin-induced apoptosis by targeting GAS6-AKT in SKOV3 ovarian cancer cells

Platinum-based (especially cisplatin) chemotherapy is the main treatment after surgery for ovarian cancer. Although the initial treatment is effective, chemotherapy resistance develops rapidly. Therefore, chemotherapy resistance has always been a huge obstacle in the treatment of ovarian cancer. Staphylococcal nuclease domain-containing protein 1 (SND1) is an evolutionarily conserved multifunctional protein that plays a role in promoting tumorigenesis under various stress states. In this study, using MTT and SKOV3 ovarian cancer cells deficient in SND1 were observed to be more apoptotic and to express more apoptotic protein after treatment with cisplatin through the MTT, clone formation, and flow cytometry assays, while cells overexpressing SND1 exhibited a decreased number of apoptotic cells and expression of apoptotic proteins. Moreover, SND1 can regulate the expression of Growth arrest-specific 6 (GAS6) and then activate the AKT signaling pathway to achieve the regulation of sensitivity to cisplatin-induced apoptosis in ovarian cancer.

A bioinformatic analysis of WFDC2 (HE4) expression in high grade serous ovarian cancer reveals tumor-specific changes in metabolic and extracellular matrix gene expression

Human epididymis protein-4 (HE4/WFDC2) has been well-studied as an ovarian cancer clinical biomarker. To improve our understanding of its functional role in high grade serous ovarian cancer, we determined transcriptomic differences between ovarian tumors with high- versus low-WFDC2 mRNA levels in The Cancer Genome Atlas dataset. High-WFDC2 transcript levels were significantly associated with reduced survival in stage III/IV serous ovarian cancer patients. Differential expression and correlation analyses revealed secretory leukocyte peptidase inhibitor (SLPI/WFDC4) as the gene most positively correlated with WFDC2, while A kinase anchor protein-12 was most negatively correlated. WFDC2 and SLPI were strongly correlated across many cancers. Gene ontology analysis revealed enrichment of oxidative phosphorylation in differentially expressed genes associated with high-WFDC2 levels, while extracellular matrix organization was enriched among genes associated with low-WFDC2 levels. Immune cell subsets found to be positively correlated with WFDC2 levels were B cells and plasmacytoid dendritic cells, while neutrophils and endothelial cells were negatively correlated with WFDC2. Results were compared with DepMap cell culture gene expression data. Gene ontology analysis of k-means clustering revealed that genes associated with low-WFDC2 were also enriched in extracellular matrix and adhesion categories, while high-WFDC2 genes were enriched in epithelial cell proliferation and peptidase activity. These results support previous findings regarding the effect of HE4/WFDC2 on ovarian cancer pathogenesis in cell lines and mouse models, while adding another layer of complexity to its potential functions in ovarian tumor tissue. Further experimental explorations of these findings in the context of the tumor microenvironment are merited.

OSI-906 restores the sensitivity of ovarian clear cell carcinoma to cisplatin by targeting the IGF1R/AKT pathway

Among the various histologic subtypes of ovarian cancers (OCs), ovarian clear cell carcinoma (OCCC) represents a great challenge due to its disease aggressiveness and resistance to chemotherapy. IGF1 is overexpressed in epithelial ovarian cancer (EOC), and IGF1 pathway activation is related to the chemoresistance of various cancers. In this study, we found that the expression level of IGF1 was higher in OCCC than in the most common type of OC, high-grade serous adenocarcinoma (HGSC). Then, we investigated the role of IGF1 pathway activation in the progression of OCCC, observing that activation of the IGF1 pathway using IGF1 promoted the proliferation and migration of ES2 cells, while inactivation of the IGF1 pathway using the selective IGF1R inhibitor OSI-906 reversed the alteration mediated by IGF1. Based on the role of the IGF1 pathway in cancer chemoresistance, we proposed that OSI-906 may restore the sensitivity of OCCC to cisplatin. We first validated that IGF1 increased the IC50 value of cisplatin in ES2 cells, while OSI-906 decreased it. Then we confirmed that IGF1 decreased the apoptosis rate of ES2 cells induced by cisplatin, while OSI-906 increased it. Finally, we conducted animal experiments to investigate whether OSI-906 helps cisplatin control the growth of OCCC. As expected, OSI-906 increased the effect of cisplatin in attenuating the growth of OCCC in vivo. Therefore, we conclude that using OSI-906 may be an effective method to restore the sensitivity of OCCC to cisplatin by targeting the IGF1R/AKT pathway.

LPA3 is a precise therapeutic target and potential biomarker for ovarian cancer

Current studies have demonstrated that significant increased LPA levels to be observed in ascites in patients with ovarian cancer. Although several studies have shown that Lysophosphatidic acid (LPA) related to the progression of ovarian cancer, which LPA receptors (LPARs) and G-coupled protein subtypes mediated in LPA actions have not been clearly elucidated. This study aimed to clarify the roles of LPA and it is subtype-specific LPARs mediating mechanisms in ovarian cancer integrated using bioinformatic analysis and biological experimental approaches. The big data analysis shown that LPA3 was the only differentially expressed LPA receptor among the six LPARs in ovarian cancer and further verified in immunohistochemistry of tissue microarrays. Also found that LPA3 was also highly expressed in ovarian cancer tissue and ovarian cancer cells. Importantly, LPA significantly promoted the proliferation and migration of LPA3-overexpressing ovarian cancer cells, while the LPA-induced actions blocked by Ki16425, a LPAR1/3 antagonist treated, and LPA3-shRNA transfected. In vivo study indicated that the LPA3-overexpressing cell-derived tumors metastasis, tumors volume, and tumors mass were apparently increased in xenografted nude mice. In addition, we also observed that LPA3 was differential high expression in ovarian cancer tissue of the patients. Our studies further confirmed the LPA3/Gi/MAPKs/NF-κB signals were involved in LPA-induced oncogenic actions in ovarian cancer cells. Our findings indicated that the LPA3 might be a novel precise therapeutic target and potential biomarker for ovarian cancer.

HR-HPV viral load quality detection provide more accurate prediction for residual lesions after treatment: a prospective cohort study in patients with high-grade squamous lesions or worse

The relationship between high-risk-human-papillomavirus (HR-HPV) viral loads and residual/recurrence lesion is uncertain. This study aimed to evaluate the clinical value of HR-HPV viral loads to predict the residual/recurrence lesions among women with high-grade squamous lesions or worse (≥ HSIL) after surgery. Finally, 301 women who underwent primary screening of cervical cancer using polymerase-chain-reaction-(PCR)-reverse-dot-blot-(RDB) human papillomavirus (HPV) genotyping and cytology assays were enrolled. They received surgery and took HR-HPV viral loads with a BioPerfectus Multiplex Real-Time PCR assay. Colposcopy biopsies were performed in patients with HPV-16/18(+) and/or TCT ≥ ASCUS with HR-HPV(+). The risk of HR-HPV viral loads and potentials factors for residual/recurrence lesions were analyzed and the optimal cut-off values of HR-HPV viral loads were calculated. The significant differences were found in residual/recurrence lesions among patients with different ages, margin status, cytology and HR-HPV at 6 months (all P < 0.05). Interestingly, HPV viral loads were observed significant differences in the group of residual lesions, not recurrence group. Furthermore, except for HPV-31/33, the viral loads of HP-16/52/58 were significant differences in residual lesions. The cut-off level of HR-HPV viral loads was 5.22 copies/10,000 cells, providing viable triage for the risk of residual lesions. Compared with different follow-up methods, the HR-HPV viral loads ≥ 5.22copies/10,000 cells (HR 3.39, 95% CI 1.57-7.35) had a higher risk for developing residual lesions. HR-HPV viral loads can be a reliable predictor of residual lesions. Furthermore, women with viral loads ≥ 5.22 copies/10,000 cells may have higher risk for residual disease and should be give a more aggressive treatment and follow-up strategy.

The CXCL12/CXCR7 signalling axis promotes proliferation and metastasis in cervical cancer

C-X-C chemokine receptor 7 (CXCR7), a novel receptor of C-X-C motif chemokine ligand 12 (CXCL12), is associated with the occurrence and metastasis of various malignant tumours. However, the role, function and underlying mechanisms of CXCR7 expression in cervical cancer remain undefined. The expression level of CXCR7 was evaluated in cervical cancer samples by immunohistochemistry and real-time PCR analyses. Western blot analysis was used to examine the expression level of CXCR7 in cervical cancer cell lines. HeLa cells were genetically silenced or pharmacologically inhibited for CXCR7 or CXCR4. Transwell and CCK-8 assays were used to examine cell migration and proliferation. The expression levels of MMP2, MMP9, TIMP-1 and TIMP-2 in HeLa cells were assessed by western blot or real-time PCR. HeLa cells silenced for CXCR7 were subcutaneously injected into nude mice to form tumours. The expression of CXCR7 in nude mice was investigated by immunohistochemical staining. Tumour volumes and weights were measured. The in vivo expression levels of MMP2, MMP9, TIMP-1 and TIMP-2 were determined by western blot analysis and real-time PCR. CXCR7 was overexpressed in cervical cancer tissues and cell lines. CXCL12 was highly expressed in cervical cancer lines. CXCR7 silencing or CCX733 treatment rather than CXCR4 silencing or AMD3100 treatment suppressed the proliferation, migration and invasion of cervical cancer cells stimulated by CXCL12. In a xenograft tumour model, CXCR7 silencing or CCX733 treatment inhibited the volumes and weights of xenograft tumours. In addition, downregulation of CXCR7 decreased the expression levels of MMP2 and MMP9 but increased the expression levels of TIMP-1 and TIMP-2 in vivo. These data support the finding that the downregulation of CXCR7 suppresses the proliferation and metastasis of cervical cancer cells. Inhibition of CXCR7 may be a potential targeted therapy for cervical cancer.

The effective natural compounds for inhibiting Cervical cancer

The secondary compounds found in plants are of great importance in the treatment of many diseases in medicine and pharmacy. Some of these compounds have been reported to exhibit anticarcinogenic effects by inhibiting the growth and metastatic potential of cancer cells. Consumption of the required amount of vegetables and fruits appears to have a protective effect of these secondary compounds on cancer, since most of these drugs are synthesized from natural or natural origin compounds. Secondary compounds in medicinal plants have been found to have an antiproliferative effect by increasing the expression of p53 in cervical cancer cells and decreasing the expression of cyclin D1, one of the cell proliferation markers. The most important step in the fight against cancer is the development of drugs that are selectively targeted against tumor cells and targeting cancer cells to reduce damage to normal cells and prevent the growth and spread of cancer cells. Molecular insertion test is an effective tool for evaluating the bioactivity of possible molecules. In this study, the effect of natural compounds in some medicinal plants in inhibiting cervical cancer, the points where they are effective using docking has been investigated.

Sensitization of cervical cancer cells to radiation by the cyclin-dependent kinase inhibitor dinaciclib

Dinaciclib is a selective cyclin-dependent kinase inhibitor, but its radiosensitizing effect remains unclear. The aim of this study is to investigate the radiosensitizing effect of Dinaciclib on cervical cancer cells. Two cervical cancer cell lines, Hela and Siha, were selected, and the IC50 was determined by CCK8. The radiosensitizing effect of Dinaciclib was verified by plate cloning assay, and the G2/M phase arrest and apoptosis of IR cells were verified by flow cytometry. Immunofluorescence assay was used to verify the formation of γH2AX foci following DNA damage. Western blot was performed to detect cell cycle, apoptosis, autophagy, and DNA damage-related pathways. Dinaciclib increased the cell sensitivity to IR. IR induced G2/M phase arrest and apoptosis, and Dinaciclib enhanced this effect. Further, Dinaciclib delayed DNA repair, including non-homologous end joining repair and homologous recombination repair, and reduced the expression of DNA repair proteins Ku80 (SiHa cells), Ku70, and RAD51, as well as the expression of apoptotic marker Bcl-2. The expression of autophagy marker Beclin1 induced tumor cell death and increased the formation of DNA damage marker γH2AX foci. Dinaciclib improves the sensitivity of cervical cancer cells to IR by inducing cell cycle arrest, delaying DNA repair, and increasing apoptosis. However, further research is needed to unravel the complexity of DNA repair pathways.

Treatment of cervical cancer by electrochemotherapy with bleomycin, cisplatin, and calcium: an in vitro experimental study

Low-dose chemotherapy in advanced stages of cancer does not give a positive response in treatment. The use of high-dose antineoplastic drugs creates significant side effects. The limiting situation in treatment creates a need for new generation drugs with less side effects and new treatment methods that will enable low-dose drug use. Electroporation (EP), a phenomenon, is a technique in which the membrane permeability is increased by the establishment of hydrophilic pores in the cell membrane with short and high-voltage electrical pulses. In the present investigation study, we aimed to inspect the effects of EP plus bleomycin, cisplatin, and calcium administration (CaEP) on cell viability, apoptotic activity, gene expression p53, Bax/Bcl-2 rate mitochondrial membrane potential (ΔΨm), and cell cycle in HeLa cervical cancer cell line. The permeabilization of the membrane was evaluated in flow cytometry with the PI method, and cell viability was measured in an ELISA reader with the WST-8 method. For bleomycin and cisplatin doses applied to HeLa cells, the concentration values (IC

Who should be treated with pembrolizumab in addition to standard of care in advanced cervical cancer?

Keynote-826 study demonstrated that the addition of pembrolizumab to standard systemic therapy contributes to progression-free and overall survival in patients with persistent, recurrent, or metastatic cervical cancer receiving chemotherapy with or without bevacizumab. However, we do have some comments about the study. The lack of additional survival benefit of pembrolizumab in patients with de novo metastatic disease or in elderly patients or in patients with combined positive score (CPS) < 1 may be due to the absence of abscopal immune effects of radiotherapy or primary resistance (immunodeficiency or immune escape or immunosenescence) to adaptive immunotherapy. We believe that new studies are needed to add pembrolizumab particularly in the treatment of the patients with de novo metastatic disease, PD-L1 CPS of < 1%, and advanced cervical cancer in geriatric population.

Balstilimab and other immunotherapy for recurrent and metastatic cervical cancer

Recurrent and metastatic cervical cancer is generally treated by cisplatin, paclitaxel, and bevacizumab with limited benefit this constituting an unmet need. Immune checkpoint inhibitors, namely the inhibitors of programmed death 1 and programmed death ligand 1 have been proved to be efficacious in the treatment of patients with advanced cervical cancer. Recently, a PD-1 inhibitor, pembrolizumab was approved for such cancer. However, there is much scope of improvement of current outcome. Dual blockade of cytotoxic T lymphocyte-associated protein 4 and PD-1 is an attractive therapeutic approach. It is used in other cancers and is currently proposed for cancer cervix also. Search is on for single or combined regimen showing efficacy in multiple pathological conditions of cancer cervix irrespective presence of PD-L1 in malignant tissue. An effort to meet such unmet need has culminated in inventing new immune checkpoint inhibitors namely PD-1 inhibitor, AGEN2034 (Balstilimab) and CTLA-4 inhibitor, AGEN1884 (Zalifrelimab).They have shown meaningful and durable activity as single-agent therapy in previously treated patients with persistent R/M CC in a large phase II trial (NCT03104699) in PD-L1 + and PD-L1- tumour. Responses were found both in squamous cell carcinoma & adenocarcinoma cell types. Balstilimab plus zalifrelimab combination (NCT03495882) produced improved clinical benefit over monotherapy as evidenced by higher relative response rates and longer response duration, as well as a manageable safety profile. Interesting development of this combination and other immunotherapies in R/M CC are discussed in this ensuing review.

Girdin silencing enhances mebendazole-mediated anticancer activity: a combinatorial therapeutic strategy for ovarian cancer

Ovarian cancer is among the deadliest gynecological malignancies due to its aggressive nature and limited treatment options. Mebendazole (MBZ), a known antiparasitic drug, has shown anticancer activity in several cancer types, though its mechanisms, particularly in ovarian cancer, remain unclear. Girdin (CCDC88A), a key regulator of Akt signaling and cancer cell invasion, represents a promising therapeutic target. This study explores the combined effect of MBZ and Girdin knockdown in ovarian cancer cell lines OVCAR3 and OAW42. Cells were treated with MBZ and transfected with Girdin-targeting siRNA, either individually or in combination. Biochemical assays (migration, invasion, and clonogenicity) and immunoblotting were used to assess the molecular mechanism and protein expression. Computational techniques, including homology modeling, molecular docking, structural interaction fingerprinting (SIFt), and density functional theory (DFT), were employed to study MBZ-Girdin binding. In addition, protein-protein interaction (PPI) network analysis and KEGG pathway enrichment (visualized using Cytoscape) were conducted to understand broader molecular effects. Our results showed that both MBZ and Girdin knockdown significantly decreased Girdin levels, with the combination yielding a greater inhibitory effect. This dual approach led to marked suppression of ovarian cancer cell migration, invasion, and colony formation. Docking studies confirmed stable MBZ binding to Girdin's catalytic domain, supported by favorable binding energies and molecular interactions. This is the first study to demonstrate that MBZ's anticancer efficacy is significantly enhanced by Girdin silencing, implicating the modulation of critical oncogenic pathways.

Sericin induces apoptosis in the ovarian cancer cell line (OVCAR-3) through the miR-34a-related pathway

Human ovarian cancer is a highly aggressive malignancy in women, characterized by high mortality and poor prognosis. Dysregulation of microRNAs (miRNAs) plays a critical role in the pathogenesis of various cancers, including ovarian cancer. Among these, miR-34a functions as a tumor suppressor miRNA and represents a promising target for cancer therapy. Downregulation of miR-34a in ovarian cancer has been associated with disease initiation and progression. Sericin, a silk-derived glycoprotein, possesses diverse biological activities, including antioxidant, anti-inflammatory, and anticancer properties. The present study, for the first time, investigated the potential effects of sericin on miR-34a-mediated apoptotic pathways in the human ovarian cancer cell line OVCAR3. OVCAR3 cells were treated with sericin at concentrations of 2 mg/mL and 64 mg/mL for 48 h. The expression level of miR-34a was quantified using real-time quantitative PCR (qPCR), while the protein expression levels of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the pro-apoptotic protein Bcl-2-associated X protein (BAX) were evaluated by Western blot analysis. Sericin treatment at both 2 mg/mL and 64 mg/mL significantly upregulated miR-34a expression and increased BAX protein levels in OVCAR3 cells. Moreover, sericin at 64 mg/mL markedly decreased Bcl-2 protein expression. Given the central role of Bcl-2 in conferring resistance to anticancer therapies and the importance of apoptosis dysregulation in tumor progression and therapeutic resistance, these findings suggest sericin as a promising anticancer agent. In summary, the results indicate that sericin exerts its anticancer effect, at least in part, through activation of a miR-34a-dependent apoptotic pathway.

Anatolian propolis extracts enhance cisplatin efficacy in ovarian cancer through AKT/mTOR pathway modulation and demonstrate antibacterial and antibiofilm activities

Propolis, a natural resinous substance rich in bioactive compounds, has been traditionally used for its therapeutic properties. This study investigates the cytotoxic and anticancer effects of Anatolian propolis on ovarian cancer cells, focusing on its modulation of the AKT/mTOR pathway and its ability to enhance cisplatin efficacy. Its antimicrobial and antibiofilm properties were also assessed, addressing infection risks in immunocompromised cancer patients. In epithelial ovarian cancer (A2780) cell line, apoptosis, cell cycle progression, and cell viability were evaluated using flow cytometric analysis, propidium iodide/annexin V staining, and MTS assay, respectively. The signaling pathways were analyzed using Western blotting. The IC

Clinicopathologic feature and treatment progress of high-grade ovarian neuroendocrine tumors

High-grade Ovarian neuroendocrine tumors represent a rare subset of ovarian neoplasms characterized by aggressive behavior, poor prognosis, and early metastasis. Despite their clinical significance, the management of these tumors lacks consensus due to their low incidence. This comprehensive review encompasses literature spanning from 1991 to 2024, focusing on the clinical presentation, diagnostic criteria, differential diagnosis, prognostic indicators, treatment modalities, and recent advancements in the understanding of this condition. Notably, a substantial proportion of affected individuals present during the perimenopausal period with unilateral lesions displaying mixed histological components. Biomarkers such as CA125, CA199, and NSE hold promise for aiding in the diagnosis and screening of ovarian neuroendocrine tumors. Unfortunately, patients exhibit a dismal prognosis even diagnosed at an early stage. Primary treatment strategies predominantly involve surgical intervention coupled with etoposide-cisplatin combination chemotherapy. In cases of recurrence, second-line chemotherapeutic agents including paclitaxel, irinotecan, and doxorubicin are commonly employed alongside localized radiotherapy. While specific genetic mutations remain elusive, emerging evidence suggests potential therapeutic effect involving mTOR inhibitors, PD-1 monoclonal antibodies, and antiangiogenic agents based on isolated case reports. The exploration of representative set of mutations will help for precise targeted therapies and remains a focal point of our ongoing research efforts.

Role of ZNF334 in cervical cancer: implications for EMT reversal and tumor suppression

Zinc-finger proteins are involved in many biological processes. However, the role of Zinc-finger protein 334 (ZNF334) in cervical cancer remains unidentified. This study showed that promoter methylation of ZNF334 was responsible for its reduced expression. ZNF334 suppressed malignant biological behaviors in cervical cancer. Notably, ZNF334 reversed the EMT process both in vitro and in vivo. RNA-seq coupled with bioinformatics analysis caught P3H3 which is upregulated by ZNF334. Dual-luciferase reporter and Chromatin immunoprecipitation assays illustrated that ZNF334 directly regulate P3H3. Knockdown of P3H3 attenuated the reversal of EMT induced by ZNF334. Additionally, ZNF334 overexpression sensitized cervical cancer cells to the cytotoxic effects of paclitaxel, cyclosporine and sunitinib. In conclusions, this study illustrated that DNA methylation-based silencing ZNF334 played a vital role in cervical cancer, by regulating P3H3 in turn affects EMT. ZNF334 has the potential to become a novel diagnostic biomarker and a potential treatment target for cervical cancer.

Unlocking the ‘ova’-coming power: immunotherapy’s role in shaping the future of ovarian cancer treatment

Ovarian cancer is a prominent cancer worldwide with a relatively low survival rate for women diagnosed. Many individuals are diagnosed in the late stage of the disease and are prescribed a wide variety of treatment options. Current treatment options are primarily a combination of surgery and chemotherapy as well as a new but promising treatment involving immunotherapy. Nevertheless, contemporary therapeutic modalities exhibit a discernible lag in advancement when compared with the strides achieved in recent years in the context of other malignancies. Moreover, many surgery and chemotherapy options have a high risk for recurrence due to the late-stage diagnosis. Therefore, there is a necessity to further treatment options. There have been many new advancements in the field of immunotherapy. Immunotherapy has been approved for 16 various types of cancers and has shown significant treatment potential in many other cancers as well. Researchers have also found many promising outlooks for immunotherapy as a treatment for ovarian cancer. This review summarizes many of the new advancements in immunotherapy treatment options and could potentially offer valuable insights to gynecologists aimed at enhancing the efficacy of their treatment approaches for patients diagnosed with ovarian cancer.

Upregulation of CELSR1 expression promotes ovarian cancer cell proliferation, migration, and invasion

Cadherin epidermal growth factor and laminin-G seven-pass G-type receptor 1 (CELSR1) is a planar cell polarity protein involved in the transmission of directional cues to align either individual cells within an epithelial sheet or multicellular clusters. CELSR1 has been suggested to play a role in glioma, breast cancer, and chronic lymphocytic leukemia development; however, whether it has a role in the pathogenesis of ovarian cancer remains unknown. The aim of this study was to determine the role of CELSR1 in ovarian cancer and elucidate its underlying molecular mechanisms. By analyzing gene expression data downloaded from the Cancer Genome Atlas database, we found that CELSR1 expression was upregulated in ovarian cancer tissues compared to that in normal ovarian tissues. High CELSR1 expression levels were associated with poor prognosis in patients with ovarian cancer. Cell proliferation, scratch, and transwell assays revealed that CELSR1 promoted the proliferation, migration, and invasion of ovarian cancer cells in vitro. In addition, transcriptome sequencing analysis revealed that CELSR1 knockdown in T29H cells resulted in the dysregulation of the expression of 1320 genes. Further analysis revealed that genes involved in proliferation- and migration-associated signaling pathways were regulated by CELSR1. Our study demonstrates that CELSR1 is highly expressed in ovarian cancer cells and regulates their proliferation and migration, suggesting its potential as a diagnostic marker and therapeutic target.

Sinapic acid induces cytoplasmic stress granule formation, ER stress and apoptosis mediated anticancer activity in human endometrial cancer cell lines

This study aimed to examine the impact of molecular mechanisms in endometrial cancer cell lines (Ishikawa and HEC-1-B) treated with sinapic acid (SA), which may have effect on regulation of genes in various processes including unfolded protein response and apoptosis. The impact of SA on cell viability was assessed through the XTT assay. Expressions of genes in apoptosis and endoplasmic reticulum (ER) stress pathways were evaluated using qPCR and western blot analyses. Effects of SA on colony formation and ER structure were determined using colony assay and transmission electron microscopy (TEM) visualization. The results showed a significant upregulated expression of CASP7, CASP8, CASP9, P53, ATF6, Eif2a, HSP47, IRE1 and PERK genes in Ishikawa cells. In HEC-1-B cells, expression of CASP3, CASP8, CYCS, FAS, P53, ATF6, CALR, CHOP, Eif2a, GRP78, HSP47, IRE1 and XBP1 genes were significantly increased, however FADD levels were decreased. Western blot analysis illustrated that comparing to the control CASP9 and CASP8 protein levels were increased in Ishikawa and in HEC-1-B cell lines, respectively. SA significantly suppressed colony formation capacities in both cell lines. TEM analyses also demonstrated that SA induced cytoplasmic stress granule formation in both cell lines. Therefore, this study suggested that SA can be a potential anticancer therapeutic agent for endometrial cancer.

Exploring the role of PRDX4 in the development of uterine corpus endometrial carcinoma

Peroxicedoxin 4 (PRDX4), a member of the peroxicedoxins (PRDXs), has been reported in many cancer-related studies, but its role in uterine corpus endometrial carcinoma (UCEC) is not fully understood. In the present study, we found that PRDX4 was highly expressed in UCEC tissues and cell lines through the combination of bioinformatics analysis and experiments, and elevated PRDX4 levels were associated with poor prognosis. Knockdown of PRDX4 significantly blocked the proliferation and migration of the UCEC cell line Ishikawa and reduced degree of cell confluence. These findings highlight the oncogenic role of PRDX4 in UCEC. In addition, genes that interact with PRDX4 in UCEC were MT-ATP8, PBK, and PDIA6, and we speculated that these genes interacted with each other to promote disease progression in UCEC. Thus, PRDX4 is a potential diagnostic biomarker for UCEC, and targeting PRDX4 may be a potential therapeutic strategy for patients with UCEC.

An investigative study on the impact of DLK1 and NCoR1 knockdown by siRNA transfection on endometrial cancer proliferation: unveiling notch interactions

Endometrial cancer is the most common gynecological malignancy. Despite advances in treatment, many patients experience disease recurrence or metastasis. This study investigates the impact of siRNA-mediated gene knockdown of NCoR1 and DLK1 genes in the proliferation of endometrial cancer cell lines Ishikawa and AN3CA and normal HEK 293 cells. Cellular growth and survival before and after the treatment of predesigned siRNAs in the endometrial cancer cell lines were evidenced using fluorescent stains. The mRNA expression of BID, BAX, BCL2, Caspases 3, 8, and 9 GPR78, EGFR, VEGF, NCoR1, DLK1 and ARID1A was analyzed in the untreated HEK 293, Ishikawa, and AN3CA cell lines to substantiate the oncogenic property of Ishikawa and AN3CA cell lines. Then, to evidence the successful transfection of NCoR1 and DLK1 gene in endometrial cancer cells, the mRNA and protein expression of targeted genes before and after being transfected were also validated. As a result, the mRNA expression significantly increased in BID, BAX, BCL2, GPR78, EGFR and VEGF. On the other hand, Caspases 3, 8, and 9 were down-regulated in Ishikawa and AN3CA compared to the control cell line (HEK 293). The mRNA and protein expression of NCoR1 and DLK1 in siRNA-mediated transfection supported the reduced proliferation in endometrial cancer cells by interfering with certain pathways like Notch, MAPK, SWI/SNF, and NF-κB, which have crucial roles in the grade of receptor to the histone remodeling. With these findings, the study recommends exploring the possible role and interactions of NCoR1 and DLK1, signaling pathways that favor the progression of endometrial cancer.

LncRNA THOR promotes endometrial cancer progression through the AKT and ERK signaling pathways

The long noncoding RNA (lncRNA) THOR is highly conserved and expressed in various human cancer tissues, although its potential role and underlying mechanism in endometrial cancer (EC) remain unknown. This study aims to explore THOR's biological function and molecular mechanism in EC progression. THOR expression in EC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR) and in situ hybridization (ISH). THOR expression based on The Cancer Genome Atlas (TCGA) and clinical sample analyses was significantly higher in EC tissues than normal tissues, and higher THOR levels were closely associated with poor overall survival in EC. Additionally, a positive correlation between ISH-detected THOR expression and pathological grade was observed. CCK-8, colony formation, and transwell migration and invasion assays revealed that THOR significantly enhances the proliferation, migration, and invasion abilities of EC cells. Moreover, IGF2BP1 protein expression and ERK and AKT protein phosphorylation levels in EC cells increased significantly with THOR overexpression in EC cells. In conclusion, our findings suggest that THOR promotes EC cell growth and invasion, and IGF2BP1-mediated AKT and ERK signaling pathways activation might be involved. Clinically, THOR is significantly expressed in EC, and high THOR expression correlates with poor prognosis, making it a potential prognostic marker for EC.

Associated analysis of PER1/TUBB2B with endometrial cancer development caused by circadian rhythm disorders

Endometrial cancer (EC) is one of the most common gynecologic malignancies, and the incidence rate of night shift among women workers is higher than that in the general population. Circadian rhythm disorder, mainly rhythm gene, is related to various tumor onset, including EC. This study described the sleep/night-shift features of EC patients, explored the mechanism of the circadian clock gene PER and investigated prognostic and functional values of Per1 caused by night shift. A total of 619 subjects were enrolled and divided into two groups according to night-shift duties (rhythm group and control group), analyzed for clinical risk factors and night shift features of endometrial carcinoma. Then samples were randomly selected for sequencing and western blot were performed, and the function of overexpressed PER1 in ishikawa cells was explored. We noticed that severer EC patients experienced night-shift more frequently and with longer durations. A total of 58,174 differentially expressed genes were discovered, mainly rhythm genes and related to up and downstream regulatory genes. Western blot showed that the rhythm group had elevated protein expression of BCAS4, TUBB2B and RSPO4, and decreased expression of PER1 and PER2 in night-shift. In TCGA-EC datasets, PER1 was decreased in the EC patients with a significantly positive correlation with PER2, and higher PER1 expression indicated longer survival, opposite to TUBB2B. The research of overexpressing PER1 gene in EC ishikawa cells found that PER1 can promote apoptosis, expression of TNF-a, IL-6 and PD-1/PD-L1, inhibit the tumor invasion and expression of TUBB2B gene. Together, EC severity was associated with night-shift and rhythm disorders. The rhythm relating factors PER1, TUBB2B and tumor immune factors may regulate the mechanisms of EC onset and progression.

Genetic analysis of HPV-16 L1 gene mutations and computational screening of therapeutic inhibitors for cervical cancer treatment

Cervical cancer, the fourth most common carcinoma in women worldwide, is predominantly caused by persistent infection with high risk human papillomavirus (HR-HPV). The human papillomavirus type 16 (HPV-16) L1 capsid protein plays a crucial role in immune recognition and viral dissemination. This study aims to conduct molecular analysis of the L1 gene from HR-HPV16 samples collected in Lahore, Pakistan, and to identify potential inhibitors against the L1 protein through in-silico analysis. The L1 gene was amplified using PCR (Polymerase Chain Reaction), followed by gel purification and Sanger sequencing. Nucleotide and amino acid sequence alignments were used to assess variant regions. In silico tools, including ADMET, CB DOCK 2 and Maestro Schrodinger, were employed to evaluate different parameters of various compounds with L1 protein. The study identified mutations in L1 sequences, including V357G, V359G, S369A, AND C371W, which could impact HPV-16 behavior and cancer development. Neoechinulin was identified as a promising HPV16 L1 capsid protein inhibitor with the highest binding energy score (-7.6 kcal/mol) against the L1 protein, suggesting potential antiviral efficacy. These mutations may alter the structural integrity of the L1 protein, potentially influencing HPV-16 infectivity and its role in cervical cancer progression, while virtual screening method demonstrated a cost- effective approach for discovering biologically impactful compounds. Neoechinulin identified as a potential HPV16 L1 capsid protein inhibitor through In Silico tools, further in vitro and in vivo studies are needed to confirm its antiviral efficacy.

Small molecule inhibitors of the VEGF and tyrosine kinase for the treatment of cervical cancer

Cervical cancer accounts for most deaths due to cancer in women, majorly in developing nations. The culprit behind this disease is the human papillomavirus (HPV) which accounts for more than 90% of cervical cancer cases. The viral strains produce proteins that favor the knocking down of the apoptosis process and continuous growth of cells in the cervix leading to tumor growth. Proangiogenic growth factors, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), angiopoietins, and other endothelial growth factors (EGF), are secreted by tumor cells and the surrounding microenvironment, which further advances the development of cancer. The extracellular domain of receptor tyrosine kinases is employed by ligands (like VEGF and EGF) to engage and activate them by inducing receptor dimerization, which facilitates the cascade impact of these factors. The tyrosine kinase domains of each receptor autophosphorylate each other, activating the receptor and initiating signaling cascades that promote angiogenesis, migration, proliferation, and survival of endothelial cells. Cancer cells benefit from its modified signaling pathways, which cause oncogenic activation. Upon early cervical cancer detection, the second-line therapy strategy involves blocking the signaling pathways with VEGF and small molecule tyrosine kinase inhibitors (TKIs). This review paper highlights the genesis of cervical cancer and combating it using VEGF and tyrosine kinase inhibitors by delving into the details of the currently available inhibitors. Further, we have discussed the inhibitor molecules that are currently in various phases of clinical trials. This paper will surely enhance the understanding of cervical cancer and its treatment approaches and what further interventions can be done to alleviate the disease currently serving as a major health burden in the developing world.

Hypoxia-induced PPFIA4 accelerates the progression of ovarian cancer through glucose metabolic reprogramming

Dysregulated glycolysis promotes growth and metastasis, which is one of the metabolic characteristics of ovarian cancer. Based on bioinformatics analysis, liprin-alpha-4 (PPFIA4) is a gene associated with hypoxia, and we aimed to investigate the potential mechanism of PPFIA4 during the reprogramming of glucose metabolism in ovarian cancer cells. Currently, the cell viability of ovarian cancer cells under the hypoxia treatment was evaluated by CCK-8 assay, and cell migration and invasion were measured by transwell assay and western blot. The effects of hypoxia treatment on glucose uptake, lactate production, extracellular acidification rate (ECAR), adenosine triphosphate (ATP), reactive oxygen species (ROS), Nicotinamide adenine dinucleotide phosphate (NADPH) and its oxidized form NADP + , and oxygen consumption rate (OCR) in ovarian cancer cells were examined. Then PPFIA4 was identified through bioinformatic analysis, and the regulatory effects of PPFIA4 on glucose metabolic reprogramming. Our data suggested that hypoxia enhanced the migration and invasion ability of ovarian cancer cells in vitro, and promoted the glucose metabolic reprogramming of ovarian cancer cells. Ovarian cancer cell viability, migration, and invasion were inhibited after PPFIA4 knockdown. Inhibition of PPFIA4 inhibited hypoxic-induced glucose metabolic reprogramming in ovarian cancer cells. In addition, PPFIA4 was found to bind to hypoxia-inducible factor 1alpha (HIF1A), and HIF1A prominently induced PPFIA4 expression. Collectively, HIF1A mediated upregulation of PPFIA4 and promoted reprogramming of glucose metabolism in ovarian cancer cells. Therefore, PPFIA4 may be a therapeutic target for ovarian cancer intervention.

Small molecule heat shock protein 27 inhibitor J2 decreases ovarian cancer cell proliferation via induction of apoptotic pathways

Heat shock protein 27 (Hsp27) is an important member of the chaperone protein family and its overexpression promotes cancer cell survival. Here, we investigated the apoptosis inducer role of the J2 compound (Hsp27 inhibitor) in human ovarian cancer cell lines (SKOV3 and OVCAR-3). Cell proliferation was measured by MTT assay. The parameters of J2-Hsp27 interaction were determined with molecular docking calculation. The inhibitory effect of the J2 compound on Hsp27 chaperone activity was investigated by luciferase activity assay. Finally, the apoptotic inducer role of the J2 compound on SKOV3 and OVCAR-3 cells was determined by RT-PCR and caspase-3 activity assay. J2 compound decreased SKOV3 and OVCAR-3 cell proliferation in a dose-dependent manner at 48 h with IC

A novel TREM1/DAP12-based multiple chain CAR-T cell targets PTK7 in ovarian cancer therapy

While CAR-T cell therapy has shown success against hematological tumors, its effectiveness for solid tumors, including ovarian cancer, remains unsatisfactory. This study aimed to develop and evaluate the efficacy of novel chimeric antigen receptor T (CAR-T) cells targeting PTK7 through TREM1/DAP12 signaling against ovarian cancer. The expression of PTK7 in ovarian cancer tissues and cells was evaluated using immunohistochemical staining and flow cytometric analysis. The anti-tumor effects of PTK7 CAR-T cells were assessed in vitro using real-time cell analysis and enzyme-linked immunosorbent assay, and in vivo using a xenograft tumor model. PTK7 was significantly expressed in ovarian cancer tissues and cells. PTK7-targeting CAR-T cells based on TREM1/DAP12 signaling exhibited potent cytotoxicity against ovarian cancer cells expressing PTK7 in vitro, and effectively eradicated tumors in vivo. Our findings suggest that TREM1/DAP12-based PTK7 CAR-T cells have potential as a treatment strategy for ovarian cancer. Further studies are needed to evaluate the safety and efficacy of this approach in clinical trials.

FAK inhibitor PF-562271 inhibits the migration and proliferation of high-grade serous ovarian cancer cells through FAK and FAK mediated cell cycle arrest

Focal adhesion kinase (FAK) is a promising therapeutic target for various cancers and its inhibitor development is in full swing. PF-562271 is a classic FAK inhibitor that has shown promising preclinical data and has been found to exhibit an anti-migration effect on some cancer cells. However, its anticancer effect on high-grade serous ovarian cancer (HGSOC) has not been reported. In this study, we evaluated the anti-migration and anti-proliferation effects of PF-562271 against HGSOC SKOV3 and A2780 cells, as well as the underlying mechanism. The results demonstrated that FAK was overexpressed in clinical HGSOC tissues and was positively correlated with the pathological progression of HGSOC. Moreover, HGSOC patients with high FAK expression levels exhibited low survival rates. PF-562271 treatment significantly inhibited the cell adhesion and migration of SKOV3 and A2780 cells by inhibiting p-FAK expression and decreasing the FA surface area. Additionally, PF-562271 treatment inhibited colony formation and induced cell senescence through G1 phase cell cycle arrest mediated DNA replication inhibition. Taken together, the findings demonstrated that FAK inhibitor PF-562271 significantly inhibits HGSOC cell adhesion, migration, and proliferation process through FAK and/or FAK mediated cell cycle arrest, and suggested that PF-562271 could serve as a potential oncotherapeutic agent for HGSOC targeting treatment.

SRC-3/TRAF4 facilitates ovarian cancer development by activating the PI3K/AKT signaling pathway

Abstract Objective Ovarian cancer is the seventh most common cancer in women, and it causes many deaths in women worldwide. Patients with ovarian cancer have a poor prognosis and low survival rate. This study aimed to explore the role of the SRC-3/TRAF4/PI3K/AKT pathway in ovarian cancer development. Methods SRC-3 and TRAF4 expression in ovarian cancer cell lines were assessed using qRT-PCR and western-blotting. The expression of SRC-3 and TRAF4 in ovarian cancer cells was downregulated by transient transfection with sh-RNAs. An MTT assay was performed to evaluate cell proliferation. Cell migration and invasion were measured using a Transwell assay. Cell stemness was detected using a cell spheroidization assay and western blotting. The expression levels of stem cell factors and PI3K/AKT pathway proteins were determined by qRT-PCR and western blot analysis. Results SRC-3 and TRAF4 were upregulated in ovarian cancer cell lines. TRAF4 is a downstream factor of SRC-3, and the protein level of TRAF4 was regulated by SRC-3. SRC-3 knockdown reduced TRAF4 expression. Silencing SRC-3 or TRAF4 inhibited cell proliferation, migration, and invasion, as well as the expression of stem cell factors. Furthermore, sh-TRAF4 as well as treatment with LY294002, the PI3K/Akt inhibitor, inhibited the phosphorylation of Akt and PI3K, thus repressing the activation of PI3K/AKT signaling pathway in ovarian cancer cell lines. However, TRAF4 overexpression reversed the effect of SRC-3 silencing on cell proliferation, migration, invasion, and stemness. Conclusion Our study demonstrated that SRC-3/TRAF4 promotes ovarian cancer cell growth, migration, invasion, and stemness by activating the PI3K/AKT pathway.

Enhancing the therapeutic potential of FDA-approved ifosfamide and 5-fluorouracil through rational chemical modifications for endometrial cancer treatment

Abstract Endometrial or uterine cancers predominantly occur in postmenopausal women, thereby establishing a strong correlation with advanced age. The chemotherapeutic agents ifosfamide and 5-fluorouracil have demonstrated notable efficacy against endometrial cancer by inhibiting cell division and proliferation. Nevertheless, current pharmacological treatments encounter challenges related to drug resistance and adverse effects. To assess the potential of drug modifications, in silico methodologies were employed to alter the molecular structures of ifosfamide and 5-fluorouracil with the aim of enhancing their efficacy and binding affinity to type 1 endometrial cancer. The three-dimensional configurations of mutated KRAS proteins were sourced from the Protein Data Bank. The molecular structures of ifosfamide and 5-fluorouracil were obtained from PubChem and EMBL-EBI, and subsequently modified using Chemsketch. The modifications included the addition of a methyl group, benzene ring, nitrogen atom, cyclopentane ring, and fluorine atoms to the drugs. The binding affinities of these modified drugs to the proteins were visualized using AutoDock Vina. The modified drugs exhibited improved binding affinities of −7.4 and −7.5 kcal/mol with both mutated target proteins. SwissADME analysis and Molinspiration’s evaluation of Lipinski’s rule parameters suggested that these modified drugs hold promise for the treatment of type 1 endometrial cancer, pending preclinical and clinical trials. This study represents a significant advancement in drug modification as a potential chemotherapeutic strategy for endometrial cancer. Among the two modified drugs, altered 5-fluorouracil demonstrated superior binding affinity and pharmacokinetic properties, rendering it a promising candidate.

In vitro cytotoxic and apoptotic effects of boric acid on endometrial adenocarcinoma cell lines (HEC-1B and Ischikawa)

Abstract Endometrial carcinoma, the most common malignancy of the female genital tract, remains challenging to treat despite early-stage dominance. Surgical interventions and irradiation are insufficient for advanced endometrial cancer. Our aim was to investigate to explore the in vitro cytotoxicity and apoptotic effects of boric acid (BA) on endometrial adenocarcinoma cell lines (Ishikawa and HEC-1B cell lines), providing experimental evidence for the potential application of boric acid as an anticancer drug. Time- and dose-dependent cell viability was determined with the XTT cell proliferation test. Differences in mRNA levels were determined by RT-PCR using cDNAs and SYBR green assay. Colony formation and the effect of BA on wound healing were evaluated. Immunocytochemistry and TUNEL tests were performed to evaluate apoptosis. BA increased the expression of Caspase 3 and Bax in HEC-1B and Ischikawa cell lines. It was determined that BA significantly decreased the number of colonies in both cell lines (p &lt; 0.05). In HEC-1B and Ishikawa cell lines, there was an increase in cell migration in the control group at 16 and 24 h. The apoptotic index was higher in the BA group, although it was not statistically significant. According to immunohistochemistry results, Caspase 3 and Bax expression in HEC-1B and Ishikawa cell lines were statistically increased in BA group. The expression of Bcl-2 was decreased statistically with BA treatment in both cell lines (p = 0.0001). BA treatment inhibited cell migration and colony formation, which are important for carcinogenesis, in endometrial adenocarcinoma cell lines. This inhibition was shown to occur through the apoptotic pathway.

CEBPB regulates ERK1/2 activity through SOS1 and contributes to ovarian cancer progression

Ovarian cancer (OC) is among the most prevalent malignant tumors affecting the female reproductive system. Notably, CEBPB has emerged as a highly promising biomarker, attracting substantial attention for its role in mediating chemotherapy resistance to PARP inhibitors (PARPi). However, the precise mechanism of action of CEBPB in OC remains poorly understood. CCK-8 assays, colony formation assays, transwell assays, and wound healing assays were employed to assess malignant behaviors of OC cells. Flow cytometry was utilized to analyze cell apoptosis and cell cycle progression. qRT-PCR and Western blot analyses were performed to quantify the levels of SOS1 and phosphorylated ERK1/2 (p-ERK1/2). Overexpression of CEBPB enhanced the proliferation, colony formation ability, invasion, migration, and cell cycle progression of SKOV3 and A2780 OC cells, while simultaneously inhibiting their apoptosis. Conversely, knockdown of CEBPB produced opposite effects (p < 0.01). Results from the MAPK Signaling Pathway PCR Array and Western blot analyses indicated that CEBPB increases the expression of SOS1 (p < 0.01). Additionally, dual-luciferase reporter assays demonstrated that CEBPB binds to the promoter sequence of the target gene SOS1. CEBPB knockdown significantly inhibited the malignant behavior of OC cells and reduced the levels of p-ERK1/2, whereas overexpression of SOS1 partially reversed this effect (p < 0.01). In xenograft models, CEBPB activates ERK1/2 via SOS1 upregulation, which subsequently promotes tumor growth and suppresses apoptosis (p < 0.01). CEBPB regulates ERK1/2 activity through SOS1 and contributes to OC progression.

Tβ4–17 peptide enhances the chemo-sensitivity of ovarian cancer cells to DDP by affecting NF-κB signaling pathway

Ovarian cancer is a gynecologic malignancy with high mortality and poor prognosis. Chemoresistance is a key cause of ovarian cancer recurrence and metastasis. It has been found that some bioactive peptides can inhibit the growth and metastasis of cancer cells and promote cell apoptosis, thus exerting anti-cancer effects. Tβ4-17 is a small polypeptide that we selected using ITRAQ technology, and its precursor protein is thymosin β4. This study mainly investigated its effect in combination with cisplatin (DDP) on the proliferation, migration and apoptosis of ovarian cancer resistant cells and related molecular mechanisms. Our results showed that Tβ4-17 peptide combined with DDP significantly inhibited the proliferation and migration of drug resistance cells in ovarian cancer, promoted apoptosis, and increased the chemo-sensitivity of ovarian cancer cells to DDP. In addition, qRT-PCR and Western blot showed that NF-κB was significantly highly expressed in DDP-resistant cells of ovarian cancer. After application of NF-κB inhibitors and activators, Western blot, CCK8, EDU fluorescence proliferation assay, and cell scratch assay showed that Tβ4-17 peptide down-regulated NF-κB p65 protein expression and inhibited cell proliferation and migration. In conclusion, our study demonstrates that Tβ4-17 peptide enhances the sensitivity of ovarian cancer cells to DDP by down-regulating NF-κB expression.

Advances in platinum-based cancer therapy: overcoming platinum resistance through rational combinatorial strategies

Abstract Platinum-based cancer therapy remains a cornerstone of first-line treatment for several solid tumours such as ovarian, testicular, and non-small cell lung cancers, where it has received regulatory approval as both monotherapy and combination regimens. However, the inevitable emergence of resistance has necessitated extensive preclinical and clinical efforts to develop rational platinum-based combinations. The most appealing candidates for combination therapy are those that offer additive and/or synergistic effects without undesirable overlapping toxicities. Whilst early strategies focussed on co-administration with cytotoxic chemotherapies, recent advances have shifted towards combinations with targeted therapies and immunotherapies, offering improved efficacy and durability of response. In this review, we provide a comprehensive analysis of recent clinical trials evaluating platinum-based combination strategies (excluding radiotherapy) and give an overview of trial concepts that will lead to more refined therapies for cancer. We also highlight emerging dual-drug codelivery nanosystems, platinum-based antibody–drug conjugates (ADCs), and multi-targeted platinum compounds with promising preclinical and/or clinical evidence. Beyond traditional drug pairings, the improved design strategies of new platinum compounds such as their incorporation into ADCs offer enhanced targeting and reactivity. Whilst promising preclinical examples like trastuzumab-Pt(II) and cetuximab-C8Pt(IV) bring optimism to combinatorial approaches, significant challenges including stability and controlled payload release remain to be addressed before clinical translation. By integrating advances in molecular profiling and rational drug development, platinum-based therapies continue to evolve, offering renewed optimism for overcoming drug resistance and improving patient outcomes, although challenges such as biomarker identification, toxicity management, and treatment costs remain to be fully addressed. Graphical abstract

Two-stage inertial microfluidics enrichment of activated T-cells towards a bead-less chimeric antigen receptor manufacturing protocol

Abstract CAR-T cell therapy is leading the way in the field of cancer cell immunotherapies due to its high success rates. However, the manufacturing of CAR-T cells remains complex and expensive. T-cell enrichment from patient apheresis starting material is a key step in the manufacture but cellular impurities interfere with the ex vivo transduction of T-cells and their proliferation. Current enrichment methods including magnetic bead selection suffer from various limitations. We report here a bead-less T-cell enrichment process through a two-stage procedure based on inertial microfluidics. Using apheresis like starting material samples from healthy donors, the dual-stage process showed an efficient 87% (SD ± 6%) enrichment and 80% (SD ± 30%) recovery of T-cells. Validation of the process with ovarian cancer samples resulted in a T-cell purity 70% (SD ± 10%) from a starting purity of 48% (SD ± 6%) at a 64% (SD ± 4%) T-cell recovery. The two-stage inertial microfluidic process was also shown to have no detectable effect on the proliferation of the cells.

In vitro chemo-preventive efficacy of synthetic progestin Norethindrone in human epithelial ovarian cancer

Progestin-only based oral contraceptives are majorly used as 'minipill' to prevent unintended pregnancy and treat conditions like polycystic ovary syndrome, hirsutism, and acne. However, the dearth of literature has constrained our comprehension of the exogenous progestin in relation to ovarian cancer progression. Therefore, the aim of the present study was to evaluate the chemo-preventive potential of synthetic progestin Norethindrone (NET) in epithelial ovarian cancer in vitro. Briefly, SKOV3 cells were treated with 1, 10 and 100 µM concentrations of NET for seven days period. The assays for cell viability, wound-healing, cell cycle progression, detection of reactive oxygen species (ROS) and apoptosis were executed to illustrate the protective role of NET. To further clarify the underlying process, quantitative analysis of mRNA levels of oncogenes linked to angiogenesis, inflammation, proliferation, and metastasis (VEGF, HIF-1α, COX-2, and PGRMC1) and tumour suppressor (TP53) genes was conducted. Our study revealed that NET treatment significantly reduced SKOV3 cell growth by inducing cell cycle arrest at G2/M phase, elevating ROS levels, triggering cell death via apoptosis and necrosis, and inhibiting cell migration in a dose-dependent manner. Notably, NET also upregulated TP53 expression while concurrently downregulating VEGF, HIF-1α, COX-2, and PGRMC1 expression. Our results demonstrated that the chemo-preventive effect of Norethindrone may originate from the interaction of genes which exert a protective effect against ovarian carcinogenesis. The current findings also support further investigation, which may lead to changes in prescription practices or health-related advice for women.

Up and away with cervical cancer: IL-29 is a promising cytokine for immunotherapy of cervical cancer due to its powerful upregulation of p18, p27, and TRAILR1

Cervical cancer is one of the most common types of female cancers worldwide. IL-29 is an interesting cytokine in the IFNλ family. Its role in the pathogenesis of neoplasia is complicated and has been studied in other cancers, such as lung cancer, gastric cancer, and colorectal cancer. IL-29 has been previously reported to promote the growth of pancreatic cancer. However, the direct role of IL-29 in cervical cancer has not been studied yet. This study was performed to investigate the direct effect on cervical cancer cell growth. Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the effects of IL-29 on cell survival, proliferation, and apoptosis of a well-studied cervical cancer cell line, SiHa. We further investigated the potential molecular mechanisms by using RT-PCR and IHC. We found that the percentage of colonies of SiHa cells was decreased in the presence of IL-29. This was consistent with a decreased OD value of cancer cells. Furthermore, the relative caspase-3 activity in cancer cells increased in the presence of IL-29. The anti-proliferative effect of IL-29 on cancer cells correlated with increased expression of the anti-proliferative molecules p18 and p27. The pro-apoptotic effect of IL-29 on cancer cells correlated with increased expression of the pro-apoptotic molecule TRAILR1. IL-29 inhibits cervical cancer cell growth by inhibiting cell proliferation and promoting cell apoptosis. Thus, IL-29 might be a promising cytokine for immunotherapy of cervical cancer.

Insights into ovarian cancer: chemo-diversity, dose depended toxicities and survival responses

Ovarian cancer has been one of the serious concerns for female health and medicinal practitioner all over the world. The wellness of over cancer patient is associated with survival responses which depends on many factors including chemotherapeutic diversity; treatment protocol; dose-dependent toxicity such as hematological toxicity and non-hematological toxicity. We found that the studied treatment regimens (TRs) (1-9) showed varying degree of hematological toxicities like moderate neutropenia ( 20%), negligible leucopenia, critical leucopenia (> 20%), moderate thrombocytopenia ( 20%), moderate anemia ( 20%). The studied TRs showed varying degree of non-hematological toxicities like moderate nausea-vomiting ( 20%), moderate alopecia ( 20%), moderate fatigue ( 20%), moderate neurotoxicity ( 20%), moderate diarrheas ( 35%), remarkable overall responses (> 60%), critical overall responses ( 20%), critical stable disease (< 20%) and moderate progressive disease (< 20%). Out of the studied TRs 1-9, in case of TR 6, moderate non-hematological toxicity (NHT) and effective survival response (SR) is being diluted by critical hematological toxicity (HT). On the other hand, TR 8, 9 is showing critical HT, NHT and SR. Our analysis revealed that the toxicity of the existing therapeutic agents can be controlled through judicious decision of drug administration cycles and combination therapies.

Stem cell-assisted enzyme/prodrug therapy makes drug-resistant ovarian cancer cells vulnerable to natural killer cells through upregulation of NKG2D ligands

Cancer stem-like cells (CSCs) are believed to be responsible for cancer recurrence and metastasis. Therefore, a therapeutic approach is needed to eliminate both rapidly proliferating differentiated cancer cells and slow-growing drug-resistant CSCs. Using established ovarian cancer cells lines as well as ovarian cancer cells isolated from a patient with high-grade drug-resistant ovarian carcinoma, we demonstrate that ovarian CSCs consistently express lower levels of NKG2D ligands (MICA/B and ULBPs) on their surfaces, a mechanism by which they evade natural killer (NK) cells' surveillance. Here, we discovered that exposure of ovarian cancer (OC) cells to SN-38 followed by 5-FU not only acts synergistically to kill the OC cells, but also makes the CSCs vulnerable to NK92 cells through upregulation of NKG2D ligands. Since systemic administration of these two drugs is marred by intolerance and instability, we engineered and isolated an adipose-derived stem cell (ASC) clone, which stably expresses carboxylesterase-2 and yeast cytosine deaminase enzymes to convert irinotecan and 5-FC prodrugs into SN-38 and 5-FU cytotoxic drugs, respectively. Co-incubation of ASCs and prodrugs with drug-resistant OC cells not only led to the death of the drug-resistant OC cells but also made them significantly vulnerable to NK92 cells. This study provides proof of principle for a combined ASC-directed targeted chemotherapy with NK92-assisted immunotherapy to eradicate drug-resistant OC cells.

Curcumin suppresses malignant behaviors of ovarian cancer through regulation of tumor-associated macrophages

Curcumin, a natural polyphenol with established anti-tumor properties, has shown therapeutic potential in ovarian cancer. However, its mechanisms, particularly through modulation of tumor-associated macrophages (TAMs) in the tumor microenvironment, remain unexplored. This study aimed to elucidate how curcumin suppresses ovarian cancer progression by regulating TAM polarization. Primary TAMs isolated from ascites of ovarian cancer patients were co-cultured with SKOV3/OVCAR-3 cancer cells. Curcumin was administered at varying doses (5-80 μM) to assess its direct effects on cancer cell viability and its indirect effects via TAM modulation. Epithelial-mesenchymal transition (EMT), migration, invasion, and cytokine profiles were analyzed using CCK-8, flow cytometry, RT-PCR, Western blot, and functional assays. High-dose curcumin (40-80 μM) directly inhibited cancer cell proliferation. In contrast, low-dose curcumin (5-20 μM) suppressed TAM-induced malignant behaviors: it reduced M2 polarization (CD206⁺ TAMs decreased by 54.89% to 32.14%, p < 0.01) while increasing M1-associated cytokines (IL-12↑, IL-1β↑) and decreasing M2 markers (IL-10↓, TGF-β↓). TAM-conditioned medium primed with 20 μM curcumin significantly attenuated cancer cell migration (scratch closure: 65% vs. 85% in TAM-only group, p < 0.01), invasion, and EMT (E-cadherin↑, N-cadherin↓, Vimentin↓). Our study uncovered the mechanism of the anti-tumor effect of curcumin in low doses related to the regulation of TAMs, which might provide novel insight into the treatment of ovarian cancer.

Immunotherapies landscape and associated inhibitors for the treatment of cervical cancer

Cervical cancer ranks as the fourth most common form of cancer worldwide. There is a large number of situations that may be examined in the developing world. The risk of contracting HPV (Human Papillomavirus) due to poor sanitation and sexual activity is mostly to blame for the disease's alarming rate of expansion. Immunotherapy is widely regarded as one of the most effective medicines available. The immunotherapy used to treat cervical cancer cells relies on inhibitors that block the immune checkpoint. The poly adenosine diphosphate ribose polymer inhibited cervical cancer cells by activating both the programmed death 1 (PD-1) and programmed death ligand 1 (CTLA-1) checkpoints, a strategy that has been shown to have impressive effects. Yet, immunotherapy directed towards tumors that have already been invaded by lymphocytes leaves a positive imprint on the healing process. Immunotherapy is used in conjunction with other treatments, including chemotherapy and radiation, to provide faster and more effective outcomes. In this combination therapy, several medications such as Pembrolizumab, Durvalumab, Atezolizumab, and so on are employed in clinical trials. Recent developments and future predictions suggest that vaccinations will soon be developed with the dual goal of reducing the patient's susceptibility to illness while simultaneously strengthening their immune system. Many clinical and preclinical studies are now investigating the effectiveness of immunotherapy in slowing the progression of cervical cancer. The field of immunotherapy is expected to witness more progress toward improving outcomes. Immunotherapies landscape and associated inhibitors for the treatment of Cervical Cancer.

EGCG attenuate EGF triggered matrix abundance and migration in HPV positive and HPV negative cervical cancer cells

Our previous laboratory findings suggested the beneficial effects of epigallocatechin gallate (EGCG) against cervical cancer (CC) cells survival. The present study is aimed at identifying the effects of EGCG in preventing the actions of epidermal growth factor (EGF) in human papilloma virus (HPV) 68 positive ME180 and HPV negative C33A CC cells. An elevated level of EGF in tumor micro-environment (TME) is linked to the metastasis of several cancers including CC. We hypothesized that EGCG has the ability to block the actions of EGF. To test this, survival assay was performed in cells treated with or without EGF and EGCG. The mitochondrial activity of cells was ascertained using MTT assay and mitored staining. Protein and non-protein components in the extracellular matrix such as collagen and sulphated glycosaminoglycans (GAGs) were evaluated using sirius red and alcian blue staining, respectively. Matrix metalloproteinase-2 (MMP-2) gene expression and enzymatic activity were assessed using real time-reverse transcriptase-polymerase chain reaction (RT-PCR) and gelatin zymography. Wound healing assay was performed to assess the EGF induced migratory ability and its inhibition by EGCG pre-treatment. Clonogenic assay showed that EGCG pre-treatment blocked the EGF driven colony formation. In silico analysis performed identified the efficacy of EGCG in binding with different domains of EGF receptor (EGFR). EGCG pre-treatment prevented the epithelial-mesenchymal transition (EMT) and metabolic activity induced by EGF, this is associated with concomitant reduction in the gene expression and enzyme activity of MMP-2. Further, reduced migration and ability to form colonies were observed in EGCG pre-treated cells when stimulated with EGF. HPV positive ME180 cells showed increased migratory and clonogenic ability upon EGF stimulation, whose effects were not much significant in HPV negative C33A cells. EGCG effectively blocked the actions of EGF in both HPV positive and HPV negative conditions and can be advocated as supplementary therapy for the management of EGF driven CC. However, further studies using cell line-derived xenograft (CDX)/patient-derived xenograft (PDX) model system is warranted to validate the therapeutic utility of EGCG.

The effects of STA-9090 (Ganetespib) and venetoclax (ABT-199) combination on apoptotic pathways in human cervical cancer cells

Combined chemotherapy is recommended strategy as a first-line treatment method in patients with cervical cancer. Ganetespib (STA-9090) is a second-generation heat shock protein 90 (Hsp90) inhibitor that blocks the ATPase function of Hsp90 and inhibits the proper folding of oncogenic client proteins. Venetoclax (ABT-199) is an orally bioavailable Bcl-2 (B-cell lymphoma 2) inhibitor that stimulates apoptotic signaling pathways in cancer cells. This study evaluated the anticancer effects of STA-9090 combined with Venetoclax in the human cervical cancer cell line (HeLa). The human cervical cancer cells were treated with STA-9090, Venetoclax, and Sta-9090 plus Venetoclax for 48 h, and cell viability was measured using the XTT assay. The alteration of the Hsp90 protein expression level and the chaperone activity of HSP90 were detected by ELISA and luciferase aggregation assay, respectively. For the apoptotic process, qRT-PCR was applied to study Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 1 (Bcl-xL ), Cytochrome c (Cyt-c), Caspase3 (Cas-3), and Caspase7 (Cas-7) expression levels after drug treatments. Also, a colorimetric Cas-3 activity assay was performed to detect the induction of the apoptosis process. Our results demonstrated that 8 nM of STA-9090 combined with 4 µM of Venetoclax synergistically inhibited cervical cancer cell proliferation more than STA-9090 or Venetoclax alone after 48 h of treatment. STA-9090 and Venetoclax combination decreased the protein expression level of Hsp90 and significantly inhibited chaperone activity of Hsp90. This combination stimulated apoptosis in cervical cancer cells by down-regulating of anti-apoptotic markers while inducing pro-apoptotic markers. Also, the STA-9090-Venetoclax combination increased Cas-3 activity in Hela cells. Collectively, these findings pointed out that the STA-9090-Venetoclax combination exhibited more activity than the individual drugs to stimulate toxicity and apoptosis in cervical cancer cells based on HSP90 inhibition.

Melatonin synergistically enhances docetaxel induced endoplasmic reticulum stress to promote apoptosis by suppressing NF‐κB activation in cervical cancer

Cervical cancer is the fourth most common malignancy in women globally. Although chemotherapy significantly improves the survival of cervical cancer patients, the development of drug resistance is inevitable. In the present study, our study showed that melatonin suppressed the proliferation, cell survival, colony formation, and the ability of adhering to fibronectin in cervical cancer cells. Our data suggested that docetaxel insensitivity was caused by NF-κB pathway activation, and followed by reducing endoplasmic reticulum stress and apoptosis. We showed that melatonin functioned as an oncostatic agent via inhibition of NF-κB signaling in cervical cancer cells. Interestingly, melatonin not only reduced the basal and inducible NF-κB pathway activation, but also prevented docetaxel induced NF-κB pathway activation by stabilizing IκBα protein. Importantly, inhibition of NF-κB pathway activation by melatonin abrogated the protective effect of NF-κB activation on docetaxel provoked endoplasmic reticulum stress, and further enhanced endoplasmic reticulum stress and apoptosis to produce synergistic oncostatic effects in cervical cancer cells. In summary, we revealed that melatonin was a novel agent to enhance docetaxel sensitivity by abolishing NF-κB activation and aggravating endoplasmic reticulum stress. Our results might provide a rationale for the clinical application of melatonin to overcome docetaxel resistance in cervical cancer patients.

Efficacy and safety of EGFR inhibitor gefitinib in recurrent or metastatic cervical cancer: a preliminary report

AbstractThere has been growing interest in the use of epidermal growth factor receptor inhibitors in various cancers. The study was conducted to evaluate the efficacy and safety of gefitinib as a monotherapy in patients with recurrent or metastatic cervical cancer. Patients with cervical carcinoma who experienced locoregional recurrence or distant metastases either at presentation or after definitive combined chemoradiotherapy or postoperative radiotherapy were enrolled. Gefitinib was administered orally at a dose of 250 mg/d to eligible patients. Treatment with Gefitinib was continued until disease progression, intolerable adverse effects were developed, or consent was withdrawn. Clinical and radiological investigations were used to verify the disease response. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The study enrolled 32 patients who met the eligibility criteria. Thirty patients were available for the analysis. The majority of the patients included in the analysis had FIGO stage IIIB disease at their initial presentation. The median follow-up time was 6 months (3–15 months). Two patients (7%) had a complete clinical response, 7 patients (23%) had a partial response, 5 patients (17%) showed a stable disease and 16 patients had progressive disease (53%). The disease control rate was 47%. The median PFS was noted to be 4.5 months and the 1-year PFS was 20%. None of the individuals experienced toxicity of grade 3 or higher. All toxicities were managed conservatively. The study suggests that gefitinib may be a promising therapeutic option for patients with advanced cervical cancer who have limited treatment alternatives.

The “collateral damage” of the war on COVID-19: impact of the pandemic on the care of epithelial ovarian cancer

The covid-19 pandemic has impacted the management of non-covid-19 illnesses. Epithelial ovarian cancer (EOC) requires long-duration multidisciplinary treatment. Teleconsultation and shared care are suggested solutions to mitigate the consequences of the pandemic. However, these may be challenging to implement among patients who come from the lower economic strata. We report the disastrous impact of the pandemic on the care of EOC by comparing patients who were treated during the pandemic with those treated in the previous year. We collected the following data from newly diagnosed patients with EOC: time from diagnosis to treatment, time for completion of planned chemotherapy, and proportion of patients completing various components of therapy (surgery and chemotherapy). Patients treated between January 2019 and September 2019 (Group 1: Pre-covid) were compared with those treated between January 2020 and December 2020 (Group 2: During covid pandemic). A total of 82 patients were registered [Group 1: 43(51%) Group 2: 39(49)]. The median time from diagnosis to start of treatment was longer in group 2 when compared to group 1 [31(23-58) days versus 17(11-30) days (p = 0.03)]. The proportion of patients who had surgery in group 2 was lower in comparison to group 1 [33(77%) versus 21(54%) (p = 0.02)]. Proportion of patients who underwent neoadjuvant (NACT) and surgery were fewer in group 2 in comparison to group 1 [9(33%) versus 18(64%) p = 0.002]. Among patients planned for adjuvant chemotherapy, the median time from diagnosis to treatment was longer in group 2 [28(17-45) days, group 1 versus 49(26-78) days, group 2 (p = 0.04)]. The treatment of patients with EOC was adversely impacted due to the COVID-19 pandemic. There was a compromise in the proportion of patients completing planned therapy. Even among those who completed the treatment, there were considerable delays when compared with the pre-covid period. The impact of these compromises on the outcomes will be known with longer follow-up.

NUC-1031, use of ProTide technology to circumvent gemcitabine resistance: current status in clinical trials

Resistance to gemcitabine chemotherapy is common in patients with pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC) and ovarian cancers (OC), conferring poor survival. Use of ProTide technology led to the development of a 'partially-activated' monophosphorylated gemcitabine compound, termed NUC-1031. NUC-1031 enters cancer cells independent of the human equilibrative nucleoside transporter, does not require deoxycytidine kinase-mediated activation and resists cytidine deaminase-mediated breakdown into toxic by-products. The phase I PRO-001 trial recruited 68 patients with advanced solid tumours; of the 49 patients that had response-evaluable disease, 5 (10%) had a partial response (PR) and 33 (67%) had stable disease (SD). Subsequently, the PRO-002 study assessed the safety and efficacy of NUC-1031 combined with carboplatin for patients with OC (n = 25); preliminary data from this study reported one (4%) unconfirmed complete response (CR), 8 (35%) PRs and 13 (57%) patients with SD, the final outcome data are awaited. The ABC-08 trial for advanced BTC assessed safety and efficacy of NUC-1031 combined with cisplatin; 14 patients were recruited with a 50% objective response rate in the intention to treat population at interim analysis. ACELARATE, the phase III trial in first-line advanced PDAC comparing NUC-1031 to gemcitabine monotherapy, recruited 200 patients but has been paused for futility analysis. Early studies demonstrate NUC-1031 is well tolerated with favourable pharmacokinetic profiles. NUC-1031 use in PDAC remains unclear, but encouraging results of disease control in BTC and OC has prompted phase II and III trial development. NuTide 121, is a phase III trial comparing cisplatin-NUC 1031 combination to the standard of care cisplatin-gemcitabine and recruitment is ongoing. Recruiting trials and mature data from existing studies will help inform on the impact of NUC-1031 on patient survival over standard gemcitabine.

A comparative analysis of phyto-components on EGFR binding, viability, and migration in HPV positive ME180 and HPV negative C33A cervical cancer cells

A need for effective implementation of cervical cancer (CC) even in developed countries insist the urge for developing an effective drug molecule to treat CC. Previously, we showed an inverse correlation between survival of CC patients and epidermal growth factor (EGF) receptor (EGFR) levels. Newer tyrosine kinase inhibitors to treat CC are being constantly pursued. In this context, the proposed study is an attempt to perform a comparative analysis using 20 phyto-components to determine the effective lead molecule. Molecular docking was utilized to determine the comparative efficacy of 20 phyto-components in binding to EGFR. It was then validated by cell viability, mitochondrial membrane potential, apoptosis, migration, and matrix metalloproteinase (MMP-2) in human papilloma virus (HPV) positive and HPV negative CC cells using top nine phyto-components based on computational screening. Computational analysis identified nine phyto-components out of which five compounds were effective in reducing the survival, mitochondrial membrane potential, apoptosis, migration, and MMP-2 secretion. EGCG, plumbagin, quercetin, emodin, and naringenin were identified as effective molecules in attenuating CC survival, proliferation, and migration.

Pterostilbene as a promising natural anticancer agent in gynecological cancers

Gynecological cancer, encompassing cancers such as endometrial and cervical cancer, is a growing concern worldwide, with a rising incidence and significant impact on women's health. Pterostilbene (PT), a natural compound, has shown promising therapeutic potential in gynecological cancer treatment. This review aims to summarize the current state of knowledge on PT's effects in gynecological cancer, focusing on its molecular mechanisms, preclinical studies, and clinical trials. A comprehensive literature search was conducted using databases, such as Google Scholar, PubMed, Wiley Online Library, Scopus, and Web of Science, covering studies published over the last 10 years (2015-2025). The search focused on PT's therapeutic potential in gynecological cancer, including its synergistic action with other therapies or natural compounds. The review highlights PT's ability to modulate key signaling pathways, induce apoptosis, and inhibit cell cycle progression in endometrial carcinoma cells and cervical cancer cells. Preclinical studies demonstrate PT's efficacy in reducing tumor size and enhancing anti-tumor activity when pterostilbene (PT) is combined with megestrol acetate (MA). Clinical trials suggest that PT combined with MA may be a promising therapeutic strategy for endometrial cancer treatment. Overall, this review provides a comprehensive overview of PT's therapeutic potential in gynecological cancer and highlights its promise as a potential treatment option. Further research is needed to fully establish PT's efficacy and safety in gynecological cancer patients. Notably, our literature search did not yield sufficient studies related to vulvar or vaginal cancers, highlighting a significant gap in the current research landscape.

Revisiting macrophages in ovarian cancer microenvironment: development, function and interaction

AbstractTumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and have been linked to immunosuppression and poor prognosis. TAMs have been shown to be harmful in ovarian cancer (OC), with a positive correlation between their high levels of tumors and poor overall patient survival. These cells are crucial in the progression and chemoresistance of OC. The primary pro-tumoral role of TAMs is the release of cytokines, chemokines, enzymes, and exosomes that directly enhance the invasion potential and chemoresistance of OC by activating their pro-survival signalling pathways. TAMs play a crucial role in the metastasis of OC in the peritoneum and ascities by assisting in spheroid formation and cancer cell adhesion to the metastatic regions. Furthermore, TAMs interact with tumor protein p53 (TP53), exosomes, and other immune cells, such as stem cells and cancer-associated fibroblasts (CAFs) to support the progression and metastasis of OC. In this review we revisit development, functions and interactions of TAMs in the TME of OC patients to highlight and shed light on challenges and excitement down the road.

PARK2 suppresses the proliferation of high-grade serous ovarian carcinoma via inducing the proteasomal degradation of ZNF703

High-grade serous ovarian cancer (HGSC) is an aggressive disease with poor prognosis. The oncoprotein ZNF703 is implicated in driving HGSC pathogenesis, but factors regulating its abundance remain unclear. In this study, we aim to investigate the potential connection between ZNF703 dysregulation and ubiquitin-mediated protein degradation in HGSC. Bioinformatics prediction was performed using BioGRID database. HGSC representative cell lines were utilized for in vitro and in vivo studies. Results showed that ZNF703 protein was stabilized upon proteasome inhibition, suggesting a regulation via ubiquitination. The ubiquitin E3 ligase PARK2 was found to interact with ZNF703 in a dose-dependent manner, promoting its polyubiquitination and subsequent proteasomal degradation. Re-expression of PARK2 in HGSC cells led to reduced ZNF703 levels together with decreased Cyclin D1/E1 abundance and G1 cell cycle arrest. ZNF703 overexpression alone increased S phase cells, Cyclin D1/E1 levels, and xenograft tumor growth, while co-expression with PARK2 mitigated these oncogenic effects. Collectively, our findings identify ZNF703 as a bona fide substrate of PARK2, reveal a tumor suppressive function for PARK2 in attenuating ZNF703-mediated G1/S transition and HGSC growth through instigating its degradation. This study elucidates a pivotal PARK2-ZNF703 axis with therapeutic implications for targeted intervention in HGSC.

Interleukin-6 serves as a critical factor in various cancer progression and therapy

IL-6 regulates epithelial ovarian cancer EMT, invasion, and metastasis by modulating Let-7c and miR-200c through the STAT3/HIF-1α pathway

Interleukin-6 (IL-6) and hypoxia-inducible factor-1α (HIF-1α) play important roles in epithelial-mesenchymal transformation (EMT) and tumor development. Previous studies have demonstrated that IL-6 promotes EMT, invasion, and metastasis in epithelial ovarian cancer (EOC) cells by activating the STAT3/HIF-1α pathway. MicroRNA (miRNA) is non-coding small RNAs that also play an important role in tumor development. Notably, Let-7 and miR-200 families are prominently altered in EOC. However, whether IL-6 regulates the expression of Let-7 and miR-200 families through the STAT3/HIF-1α signaling to induce EMT in EOC remains poorly understood. In this study, we conducted in vitro and in vivo investigations using two EOC cell lines, SKOV3, and OVCAR3 cells. Our findings demonstrate that IL-6 down-regulates the mRNA levels of Let-7c and miR-200c while up-regulating their target genes HMGA2 and ZEB1 through the STAT3/HIF-1α signaling in EOC cells and in vivo. Additionally, to explore the regulatory role of HIF-1α on miRNAs, both exogenous HIF blockers YC-1 and endogenous high expression or inhibition of HIF-1α can be utilized. Both approaches can confirm that the downstream molecule HIF-1α inhibits the expression and function of Let-7c and miR-200c. Further mechanistic research revealed that the overexpression of Let-7c or miR-200c can reverse the malignant evolution of EOC cells induced by IL-6, including EMT, invasion, and metastasis. Consequently, our results suggest that IL-6 regulates the expression of Let-7c and miR-200c through the STAT3/HIF-1α pathway, thereby promoting EMT, invasion, and metastasis in EOC cells.

Identification of a novel tRNA-derived small RNA fragment, tRF-16-2YU04DE, with the potential of inhibiting endometrial cancer progression

As the second most prevalent gynecological malignancy, the incidence and mortality of endometrial cancer (EC) are rising. Transfer RNA-derived small RNAs (tsRNAs), a novel class of non-coding RNAs, are frequently dysregulated in multiple cancers. Nevertheless, its precise roles in EC remain to be elucidated. High-throughput sequencing technology was employed to characterize the expression profiles of tsRNAs in EC and healthy controls (HCs) tissues, followed by differential expression analyses. Quantitative real-time polymerase chain reaction (RT-qPCR) was applied to identify the target tsRNA for further biological functions experiments. Bioinformatics followed with RT-qPCR and Western blot systematically explore potential target genes and delineated the underlying molecular mechanisms. Eventually, a total of 284 tsRNAs were identified in both EC and HC tissues with 26 upregulated and 47 downregulated significantly. tRF-16-2YU04DE was finally identified as the target molecule. Functional experiments revealed that the overexpression of tRF-16-2YU04DE not only inhibited the proliferation, migration, and invasion of EC cells, but also promoted apoptosis and disrupted cell cycle progression. Although the downregulation of tRF-16-2YU04DE significantly promotes the proliferation, migration, and invasion of EC cells, it does not have a notable effect on cell apoptosis or the cell cycle. Bioinformatics analyses combined with RT-qPCR and Western blot results showed KLF5 expression was particularly downregulated by the overexpression of tRF-16-2YU04DE. tRF-16-2YU04DE-inhibiting EC progression in vitro may serve as a promising therapeutic target. The underlying mechanism is likely linked to its RNA silencing function, specifically targeting the 3' untranslated region (3' -UTR) of KLF5 mRNA.

Crosstalk between microRNA and oxidative stress in ovarian cancer: diagnosis, pathogenesis and therapeutic resistance

Abstract Ovarian cancer (OC) is the most lethal gynecologic malignancy due to late-stage diagnosis, frequent recurrence, and resistance to therapy. Emerging evidence highlights oxidative stress (OS)—a redox imbalance caused by excessive reactive oxygen species (ROS)—as a key contributor to tumor development and therapy failure. This article presents a narrative review of the bidirectional relationship between oxidative stress and microRNAs (miRNAs) in OC, emphasizing their molecular crosstalk, clinical relevance, and therapeutic potential. A targeted synthesis of recent experimental and clinical studies was conducted to explore how redox biology and miRNA dysregulation contribute to OC pathogenesis and treatment resistance. ROS promotes genomic instability, epithelial–mesenchymal transition (EMT), angiogenesis, immune evasion, and chemoresistance. Redox-responsive miRNAs (e.g., miR-29b, miR-200a/c, miR-145-5p, miR-484, miR-21) regulate antioxidant defenses, DNA repair, apoptosis. OS modulates miRNA biogenesis via transcriptional and epigenetic changes, and miRNAs form feedback loops that influence ROS levels and tumor progression. Circulating and exosomal miRNAs show promise as non-invasive biomarkers, but require further clinical validation. Therapeutic approaches targeting the ROS–miRNA axis—including mimics, antagomiRs, and nanocarriers—show preclinical potential, though challenges in delivery and toxicity remain. The dynamic OS–miRNA interplay represents a novel regulatory axis in OC. Exploiting this axis may enhance early diagnosis and therapy. Future work should integrate redox profiling with miRNA expression to personalize treatment and assess performance relative to existing modalities like PARP inhibitors.