Anti-Cancer Agents in Medicinal Chemistry

Photodynamic Effects of Vitamin K3 on Cervical Carcinoma Cells Activating Mitochondrial Apoptosis Pathways

Background: Photodynamic Therapy (PDT) is a photoactivation or photosensitization process, wherein vitamin K3 (Vit K3) serves as a photosensitizer to produce Reactive Oxygen Species (ROS) against bacteria at appropriate wavelengths. In this study, we used Vit K3 treatment combined with Ultraviolet radiation A (UVA) to produce photodynamic effects on cervical cancer. Methods: The dose-concentration relationship between Vit K3 treatment and UVA on tumor cells was analyzed through the Cell Counting Kit-8 method. Then, the morphological characteristics of apoptosis cells were observed through fluorescent staining and fluorescence microscopy. Apoptosis after treatment with Vit K3 treatment, UVA, and Vit K3 treatment plus UVA was further observed through Western blot analysis, flow cytometry, and TUNEL assay. The xenograft models from HeLa cells were established for the exploration of the photodynamic effect of Vit K3 treatment on cervical cancer in vivo. Results: Vit K3 treatment plus UVA reduced tumor cell viability in a dose-dependent manner. Further studies indicated that Vit K3 treatment plus UVA can inhibit tumor growth and enhance the apoptosis of cervical cancer cells. In the combination group, the expression levels of cleaved caspase-3, cleaved caspase-9, B-cell lymphoma- extra large (Bcl-xl), and cytochrome c (cyt-c) increased obviously, whereas the expression level of Bcell lymphoma 2 (Bcl-2) decreased relative to the expression levels of UVA- or Vit K3-treated cells. In the in vivo experiments, tumor growth was inhibited significantly in the VitK3 treatment plus UVA group. Additionally, we demonstrated that the combination therapy mediated an increase in cleaved caspase-3 and cleaved caspase-9 expression and decrease in Bcl-2 expression in vivo. Conclusion: Our results showed that Vit K3 treatment combined with UVA exerted photodynamic effects on cervical cancer cells by activating mitochondrial apoptosis pathways.

Tisotumab Vedotin: The First FDA-Approved Antibody-Drug Conjugate for Cervical Cancer

Synergistic Cytotoxicity Effect of 5-Fluorouracil and SHP2 Inhibitor Demethylincisterol A3 on Cervical Cancer Cell

Background: Demethylincisterol A3 (DTA3) has been identified as an SHP2 inhibitor and suppresses the growth of many cancer cells. 5-Fluorouracil (5-FU) is widely used for the clinical treatment of various cancers. However, the combination effects of 5-FU and DTA3 on cervical cancer cells remain unknown. Objective: This study evaluates the mechanism of the combination effects of 5-FU and DTA3 in cervical cancer cells. Methods: The synergistic cytotoxic effects of 5-FU and DTA3 in cervical cancer cells were calculated. Apoptosis was analysed by flow cytometry. Western blot analyses were used to examine the related signalling pathways. Results: DTA3 and 5-FU synergized to induce apoptosis and repress proliferation of cervical cancer cells by downregulating the activation of PI3K/AKT and NF-κB signalling pathways. We provided evidence that the upregulation of SHP2 expression by transfection significantly inhibited the cytotoxicity of 5-FU and DTA3. SHP2 knockdown enhanced the anti-proliferation activity of 5-FU, indicating targeting SHP2 sensitized cervical cancer cells to 5-FU. Conclusion: Our study demonstrates that SHP2 inhibitor DTA3 and 5-FU have a synergistic cytotoxic effect on cervical cancer cells. The synergistic combination of SHP2 inhibitor and 5-FU may present a promising strategy for the treatment of cervical cancer.

Investigating the Effects of Dorema hyrcanum Root Extracts on Selective Induction of Programmed Cell Death in Glioblastoma, Ovarian Cancer and Breast Cancer Cell Lines

Background: Despite remarkable advances, cancer has remained the second cause of death, which shows that more potent novel compounds should be found. Ethnobotanical compounds have a long history of treating diseases, and several approved chemotherapeutic compounds were isolated from plants. Objective: The research aimed to evaluate the cytotoxic effects of Dorema hyrcanum root extract on ovarian, breast, and glioblastoma cells while examining its selectivity towards normal cells. Additionally, the study is directed to investigate cell death mechanisms, delineate modes of cell death, and explore intracellular ROS production. Methods: Cytotoxic effects of alcoholic, dichloromethane, and petroleum ether fractions of Dorema hyrcanum were investigated on cancer and normal cells by using MTT assay, and the concentration around IC50 values was used for flow cytometric assessment of apoptosis, evaluation of the expression of selected genes via RT-qPCR and production of ROS. Results: Methanolic extract exhibited the highest cytotoxicity, impacting A2780CP and MDA-MB-231. All fractions showed comparable effects on U251 cells. Notably, extracts displayed higher IC50 values in normal HDF cells, indicating cancer cell specificity. Flow cytometry revealed induction of apoptosis and non-apoptotic death in all three cancer cell lines. QPCR results showed upregulation of related genes, with RIP3K prominently increased in U251 glioblastoma. The DCFH-DA assay demonstrated ROS induction by the PE fraction exclusively in A2780CP cells after 30 minutes and up to 24 hours. Conclusion: Dorema hyrcanum root extracts exhibited potent anti-tumor effects against all studied cell lines. The methanolic extract demonstrated the highest cytotoxicity, particularly against A2780CP and MDA-MB-231 cells. Importantly, all fractions displayed selectivity for cancer cells over normal HDF cells. Unique modes of action were observed, with the petroleum ether fraction inducing significant non-apoptotic cell death. These findings suggest promising therapeutic potential for Dorema hyrcanum in cancer treatment with subject to further mechanistic studies.

Carvacrol Exhibits Chemopreventive Potential against Cervical Cancer Cells via Caspase-Dependent Apoptosis and Abrogation of Cell Cycle Progression

Background: The carcinogenesis of the uterine cervix is predominantly initiated with the consistent infection of the Human Papilloma Virus (HPV). Owing to the side effects of standard chemotherapeutics in the treatment of recurrent and metastatic cervical cancer, there is a need for a better and effective treatment modality. In this lieu of concern, natural compounds have proven their worthwhile potential against the treatment of various carcinomas. Carvacrol is a phenolic monoterpenoid and several reports have suggested its different biological properties including antioxidant, anti-inflammatory and anticancer activity. Objective: The objective of our present study was to investigate the effect of carvacrol on HPV18+ HeLa cervical cancer cells. Methods: HeLa cervical cancer cells were cultured and subsequently treated with various doses of carvacrol. Cell viability was assessed via MTT assay. DAPI and Hoechst3342 staining were used to qualitatively analyzed the induced apoptosis. Reactive Oxygen Species (ROS) was estimated by DCFDA staining protocol and quantitatively estimated by flow cytometry. The cell cycle distribution and apoptosis (FITC-Annexin V assay) were analyzed by flow cytometry. Results: The results of the present study have established that carvacrol strongly suppresses the proliferation of cervical cancer cells via caspase-dependent apoptosis and abrogation of cell cycle progression. Furthermore, our preliminary study also demonstrated that carvacrol exhibits a synergistic effect with chemotherapeutic drugs (5-FU and carboplatin). These initial findings implicated that natural compounds could reduce the toxic effects of chemotherapeutic drugs. Conclusion: Therefore, this investigation affirms the anti-cancer potential of carvacrol against cervical cancer cells, which could be an appendage in the prevention and treatment of cervical cancer.

SUV39H1-Mediated DNMT1 is Involved in the Epigenetic Regulation of Smad3 in Cervical Cancer

Background: Smad3 is a pivotal intracellular mediator for participating in the activation of multiple immune signal pathway. Objective: The epigenetic regulation mechanism of the positive immune factor Smad3 in cervical cancer remains unknown. Therefore, the epigenetic regulation on Smad3 is investigated in this study. Methods: The methylation status of SMAD3 was detected by Methylation-specific PCR (MS-PCR) and Quantitative Methylation-specific PCR (MS-qPCR) in cervical cancer tissues and cell lines. The underlying molecular mechanisms of SUV39H1-DNMT1-Smad3 regulation was elucidated using cervical cancer cell lines containing siRNA or/and overexpression system. Confirmation of the regulation of DNMT1 by SUV39H1 used Chromatin immunoprecipitation-qPCR (ChIP-qPCR). The statistical methods used for comparing samples between groups were paired t tests and one-way ANOVAs. Results: H3K9me3 protein which regulated by SUV39H1 directly interacts with the DNMT1 promoter region to regulate its expression in cervical cancer cells, resulting in the reduce expression of the downstream target gene DNMT1. In addition, DNMT1 mediates the epigenetic modulation of the SMAD3 gene by directly binding to its promoter region. The depletion of DNMT1 effectively restores the expression of Smad3 in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1-DNMT1 was found to correlate with Smad3 expression in accordance with the expression at the cellular level. Notably, the promoter region of SMAD3 was hypermethylated in cervical cancer tissues, and this hypermethylation inhibits the subsequent gene expression. Conclusion: These results indicate that SUV39H1-DNMT1 is a crucial Smad3 regulatory axis in cervical cancer. SUV39H1-DNMT1 axis may provide a potential therapeutic target for the treatment of cervical cancer.

Processed Products of Aconitum soongaricum Stapf. Inhibit the Growth of Ovarian Cancer Cells In vivo via Regulating the PI3K/AKT Signal Pathway

Introduction/Objective: The alkaloids of songorine, aconitine, and benzoylaconitine, as the processed products of Aconitum soongaricum Stapf., can significantly inhibit the migration and invasion of ovarian cancer cells in vitro. Herein, we studied the in vivo role and mechanism of these natural products in processed A. soongaricum Stapf. Methods: A xenograft tumor model was constructed. Tumor volumes and weights were calculated. HE staining assessed the histopathological changes of tumors. Inflammatory factors were detected using ELISA. Gene and protein expressions of E-cadherin, N-cadherin, PIK3CA, and AKT1 proteins were measured using RT-qPCR and immunohistochemistry. Protein expressions of E-cadherin, N-cadherin, PIK3CA, AKT1, p-PIK3CA, and p- AKT1 proteins were detected using western blot analysis. Results: Songorine, aconitine, and benzoylaconine significantly inhibited the growth of tumors as evidenced by decreased tumor volume and weight. The extent and scope of tumor cell necrosis were less in the songorine group compared to the vehicle group. Songorine, aconitine, and benzoylaconine significantly reduced IL-6, IL-1β, and TNF-α levels. Furthermore, songorine, aconitine, and benzoylecgonine induced down-regulation of N-cadherin and AKT1 mRNA in comparison to the vehicle group. Meanwhile, songorine, aconitine, and benzoylaconine also significantly reduced N-cadherin, p-PIK3CA, and p-AKT1 proteins, while upregulating E-cadherin protein expression in comparison to the vehicle group. These effects were further enhanced when combined with the PI3K inhibitor LY294002. Conclusion: Songorine, aconitine, and benzoylaconine may inhibit ovarian cancer growth in vivo by blocking the PI3K/AKT signaling pathway. Our findings may provide evidence for the clinical application of the processed products of Aconitum soongaricum Stapf. in ovarian cancer treatment.

Adenoviral Therapy for Cervical Cancer: From Targeted Modification to Immunotherapy

Cervical cancer is a significant global health threat, ranking as the fourth most common malignancy among women and resulting in over 300,000 deaths annually. Although screening and vaccination initiatives have led to a decline in incidence rates, treatment options for advanced or recurrent cervical cancer remain inadequate, often proving ineffective and costly. In this context, adenoviral therapy has emerged as a promising strategy to enhance therapeutic outcomes. Adenoviruses are non-enveloped viruses that can efficiently infect a wide range of cells, including tumor cells, while exhibiting a favorable safety profile, making them suitable candidates for clinical applications. Adenoviral vectors possess the unique ability to package large segments of therapeutic genes, allowing for diverse treatment approaches, including oncolytic virotherapy, which selectively targets and destroys tumor cells while stimulating robust immune responses. By engineering adenoviruses to express tumor suppressor genes such as p53, researchers can restore critical apoptotic pathways often disrupted in cervical cancer. Furthermore, genetic modifications to capsid proteins can enhance the targeting of tumor cells and reduce the immunogenicity associated with these viral vectors. Additionally, adenoviral vectors can serve as delivery systems for therapeutic vaccines against HPV oncogenes E6 and E7, promoting effective immune responses and potentially preventing disease progression. The combination of adenoviral therapy with immune checkpoint inhibitors offers a novel approach to overcoming the immunosuppressive tumor microenvironment, enhancing overall antitumor immunity. Overall, this review highlights the significant advancements in adenoviral therapy for cervical cancer, emphasizing the need for further research to optimize these strategies and translate preclinical successes into effective clinical applications. By harnessing the full potential of adenoviral vectors, we can improve treatment options for patients who have cervical cancer, paving the way for more personalized and effective therapeutic interventions.

Lumiflavin Enhances the Effects of Ionising Radiation on Ovarian Cancer Stem-Like Cells by Inhibiting Autophagy

Background: The development of Cancer Stem-like Cells (CSCs) is one of the main causes of ovarian cancer tolerance to radiotherapy. Autophagy is an adaptive process by which cells damage due to radiation. As a metabolite of riboflavin, lumiflavin can enhance the chemotherapeutic effects of cisplatin on ovarian cancer CSCs. Objective: This study aimed to investigate the synergistic effects of lumiflavin and ionising radiation on ovarian cancer CSCs and explore the association of this metabolite with autophagy. Methods:: CSCs of human ovarian cancer cell lines HO8910 were treated with lumiflavin and rapamycin and then subjected to irradiation at a cumulative dose of 8 Gy. Cell proliferation ability, clonal formation ability, apoptosis rate, autophagy changes and autophagy-related protein changes were detected. Results: Lumiflavin and ionising radiation synergistically reduced cell vitality and clone formation and increased the apoptosis of CSCs compared with irradiation alone. In addition, ionising radiation increased autophagy and the expression of associated proteins, whereas lumiflavin reduced those changes in autophagy progression. Moreover, rapamycin, an autophagy inhibitor, was observed to block the synergistic effects of lumiflavin and ionising radiation on CSC apoptosis. Conclusion: Lumiflavin can enhance the effects of ionising radiation on ovarian cancer CSCs. The mechanism by which these effects are exerted is related to blocking the autophagy pathway.

Chemoresistance in Ovarian Cancer: Prospects for New Drugs

:This review focuses on the conventional treatment, signaling pathways and various reasons for drug resistance with an understanding of novel methods that can lead to effective therapies. Ovarian cancer is amongst the most common gynecological and lethal cancers in women affecting different age groups (20-60). The survival rate is limited to 5 years due to diagnosis in subsequent stages with a reoccurrence of tumor and resistance to chemotherapeutic therapy. The recent clinical trials use the combinatorial treatment of carboplatin and paclitaxel on ovarian cancer after the cytoreduction of the tumor. Predominantly, patients are responsive initially to therapy and later develop metastases due to drug resistance. Chemotherapy also leads to drug resistance causing enormous variations at the cellular level. Multifaceted mechanisms like drug resistance are associated with a number of genes and signaling pathways that process the proliferation of cells. Reasons for resistance include epithelial-mesenchyme, DNA repair activation, autophagy, drug efflux, pathway activation, and so on. Determining the routes on the molecular mechanism that target chemoresistance pathways are necessary for controlling the treatment and understanding efficient drug targets can open light on improving therapeutic outcomes. The most common drug used for ovarian cancer is Cisplatin that activates various chemoresistance pathways, ultimately causing drug resistance. There have been substantial improvements in understanding the mechanisms of cisplatin resistance or chemo sensitizing cisplatin for effective treatment. Therefore, using therapies that involve a combination of phytochemical or novel drug delivery system would be a novel treatment for cancer. Phytochemicals are plant-derived compounds that exhibit anti-cancer, anti-oxidative, anti-inflammatory properties and reduce side effects exerted by chemotherapeutics.

Downregulation of GPR4 and TCF7 Promotes Apoptosis and Inhibits Growth and Invasion of Ovarian Cancer Cells

Background: G Protein-coupled Receptor 4 (GPR4) has been reported to play essential roles in regulating the proliferation, migration and angiogenesis of vascular endothelial cells. GPR4 is also suggested to play significant roles in the growth and angiogenesis of ovarian cancer. Objective: To explore the functions of GPR4 and Transcription Factor 7 (TCF7) in ovarian cancer. Methods: The expression levels of genes involved in Wnt signaling were validated by quantitative Real-Time- PCR (q-RT-PCR). The effects of GPR4 and TCF7 on ovarian cancer cell invasion and apoptosis were determined using soft agar, transwell assay and flow cytometric assay. Protein levels of beta-catenin, MMP-2 and MMP-9 were evaluated by Western blotting. Results: In this study, we found that GPR4 and TCF7 had the capacity to control cell division by altering cell cycle distribution, anchorage-independent growth, and directional cell motility of ovarian cancer cell A2780. Also, we showed that the knockdown of GPR4 and TCF7 in ovarian cancer cell A2780 induced significant inhibitition of cell growth and invasion, as well as the promotion of apoptosis. Downregulation of TCF7 resulted in the decreased MMP-2 and MMP-9 levels. Conclusion: The results implicate that GPR4 behaves like an oncogene and may function through WNT pathway molecule TCF7. Downregulation of GPR4 and TCF7 essentially inhibited cell growth and invasion and enhanced apoptosis of ovarian cancer cells, which may lay a foundation for ovarian cancer treatment.

Current Treatment for Cervical Cancer: An Update

Cervical cancer is the leading gynecologic health problem which is considered as the 4th most widespread tumour in women. The prevalence of this fatal ailment is emerging gradually across the globe as about 18.1 million new cancer cases have been reported in 2018. The predominance of cervical cancer has been significantly found in low and middle-income countries as cervical cancer ranks fourth for both incidence and mortality, conversely, there are no effective screening systems available. This mortal state is certainly influenced by exposure of human papillomavirus, dysregulation of caspase enzyme, elevated expression of Inhibitor Apoptotic Protein (IAP), overexpression of Vascular Endothelial Growth Factors (VEGF), active/passive smoking, and dysfunction of the immune system. Generally, the clinical trial on pipeline drugs leads to the development of some promising new therapies that are more effective than standard approaches and often unavailable outside of the clinical setting. Indeed, several biological interventions that can modulate the pathological cascade of cervical cancer are still under investigation. Thus, there is a need to further summarise the promising therapies for cervical cancer as we have accomplished in HER2-positive breast cancer by targeting HER2 therapies and immune checkpoint inhibitors in melanoma. The present report revealed the pharmacokinetic/ pharmacodynamics aspects of various pipeline drugs that are promising for the treatment of cervical cancer. Moreover, the study revealed the possible mechanism, adverse drug reaction, combined therapy and pleiotropic action of these under investigational drugs, which can further improve the therapeutic efficacy and restrict the imaginable harmful effects.

Cisplatin and Probiotic Biomass Loaded Pessaries for the Management of Cervical Cancer

Introduction: Cancer is a type of disease, in which the growth of cells is abnormal and uncontrolled. One of the most common cancers among women is cervical cancer. In India, cervical cancer is one of leading causes of cancer mortality among women 30 to 69 years of age, accounting for 17% of all cancer deaths. The work present here shows the combined effects of anticancer drug along with probiotics to circumvent the side effects associated with chemotherapy and to enhance the therapeutic effect. Material and Methods: Cisplatin and drug loaded pessaries were prepared by melt mold method using the blend of PEG’s (Polyethylene Glycol) and further characterized for various in vitro and in vivo parameters. Result and Discussion: The free radical scavenging activity of probiotic Lactobacillus rhamnosus by DPPH (2,2-diphenyl-1-picrylhydrazyl) assay was observed to be 60.77μg/mL The mean weight variation, melting time, content uniformity, friability and hardness of the prepared pessary were 1.25±0.025mg, 10.86±0.64min, 99.89±0.74, 0.25%, 2.2kg/cm2. Histopathology studies presented that the developed formulation are safe for local delivery of cisplatin. Conclusion: This study provides the basis for a combination of local delivery approach along with the beneficial effects of probiotic strain which could be better a approach for the treatment of cervical cancer.

Molecular Docking Study, Cytotoxicity, Cell Cycle Arrest and Apoptotic Induction of Novel Chalcones Incorporating Thiadiazolyl Isoquinoline in Cervical Cancer

Background: Chalcones are naturally occurring compounds found in various plant species which are widely used for the traditional popular treatments. Chalcones are distinguished secondary metabolites that are reported to display diverse biological activities such as antiviral, antiplatelet, anti-inflammatory, anticancer, antibacterial and antioxidant agents. The presence of a,ß-unsaturated carbonyl group in chalcones is assumed to be responsible for their bioactivity. In addition, heterocyclic compounds having nitrogen such as isoquinolines are of considerable interest as they constitute the core structural element of many alkaloids that have enormous pharmacological activities. Objective: The objective of this study is the synthesis and biological activity of novel chalcones incorporating thiadiazolyl isoquinoline as potential anticancer candidates. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer. Methods: An efficient one pot synthesis of novel chalcones incorporating thiadiazolyl isoquinoline has been developed. The cytotoxic activity of the novel synthesized compounds was performed against four different kinds of cancer cell lines. Results: Among all the tested derivatives, chalcone 3 has the best cytotoxic profile against A549, MCF7, and HeLa cell lines, with IC50s (66.1, 51.3, and 85.1μM, respectively). Molecular docking studies for chalcone 3 revealed that CDK2, and EGFRTK domains have strong binding affinities toward the novel chalcone 3, while tubulin-colchicine-ustiloxin, and VEGFRTK domains illustrated moderate mode of binding. Conclusion: We have developed an efficient method for the synthesis of novel chalcones incorporating thiadiazolyl isoquinoline. All compounds showed better cytotoxicity results against four kinds of cancer cell lines (A549, MCF7, HCT116, and HELA cells). The results depicted that chalcone 3 has a high and promising cytotoxic effect against HELA cell line and the mechanism of cytotoxicity was widely studied through different theoretical and experimental tools. Thus, the newly synthesized derivative 3 can be utilized as a novel chemotherapeutic compound for cervical carcinoma.

Organosulphur Compounds Induce Apoptosis and Cell Cycle Arrest in Cervical Cancer Cells via Downregulation of HPV E6 and E7 Oncogenes

Background: The quest for strong, safe and cost-effective natural antiproliferative agents that could reduce cancer has been the focus now a days. In this regard, the organosulfur compounds from garlic (Allium sativum L.), like Diallyl Sulfide (DAS) and Diallyl Disulfide (DADS), have been shown to exhibit potent antiproliferative and anticancer properties in many studies. However, the potential of these compounds against viral oncoproteins in cervical cancer has not been fully elucidated yet. Objective: The objective of this study was to analyze the antiproliferative and apoptotic properties of DADS and DAS in HPV16+ human cervical cancer Caski cell line. Methods: Caski (cervical cancer cells) were cultured and followed by the treatment of various concentrations of organosulphur compounds (DADS and DAS), cell viability was measured by MTT assay. The apoptotic assay was performed by DAPI and Hoechst3342 staining. Reactive Oxygen Species (ROS) was estimated by DCFDA staining protocol. The distributions of cell cycle and apoptosis (FITC-Annexin V assay) were analyzed by flow cytometry. Finally, gene expression analysis was performed via quantitative real time PCR. Results: Our results showed that DAS and DADS exerted a significant antiproliferative effect on Caski cells by reducing the cell viability and inducing a dose-related increment in intracellular ROS production along with apoptosis in Caski cells. DAS and DADS also induced cell cycle arrest in G0/G1 phase, which was supported by the downregulation of cyclin D1 and CDK4 and upregulation of CDK inhibitors p21WAF1/CIP1 and p27KIP1 in Caski cells. Additionally, DAS and DADS lead to the downregulation of viral oncogene E6 and E7 and restoration of p53 function. Conclusion: Thus, this study confirms the efficacy of both the organosulfur compounds DADS and DAS against cervical cancer cells.

Antiproliferative and Pro-Apoptotic Effects of Thiazolo[3,2–b][1,2,4]triazoles in Breast and Cervical Cancer Cells

Background and Objectives: Cancer is one of the leading causes of death in the world affecting millions of people. The commercially available anticancer drugs lack the selectivity and show several undue side effects during the biologically targeted therapy, thus calling for the exploration of wider chemical space to furnish new structural leads with promising anticancer potential. In this endeavor, we synthesized a series of coumarinyl thiazolotriazoles with diverse functional group tolerance and will be tested for their anticancer properties against cancer cell lines (HeLa and MCF-7) and a normal cell line (BHK-21). Materials and Methods: To overcome such complications, in the current study, we evaluated the cytotoxic effects of coumarinyl thiazolotriazole hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells i.e., Baby Hamster Kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl- 2,5-diphenyl-2H-tetrazolium bromide) assay. DNA binding studies of compound 6c was performed on Herring- Sperm DNA (HS-DNA) and docking studies were also carried out. The mechanistic studies were performed on potent compounds by fluorescent microscopic studies, release of Lactate Dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis. Results: As revealed by MTT assay, compounds 6m and 6c were identified as the most potent derivatives among the tested series with IC50 values of 5.64 and 29.1 μM against HeLa and MCF cells, respectively as compared to cisplatin which gave IC50 values of 11.3 and 6.20 μM, respectively. DNA binding studies of compound 6c showed the binding of compound in DNA with Gibbs free energy of ‒17 KJ/mol and docking studies validated the DNA binding studies. Fluorescent microscopic studies using 4′,6-diamidino-2-phenylindole (DAPI) and Propidium Iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 6m. Moreover, compounds 6m and 6c also triggered the release of Lactate Dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a luminescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 6m caused G0 /G1 arrest in the treated HeLa cells. Conclusion: Our results suggested that the compound possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer efficacy of this compound at clinical level.

Antiproliferative Activity of Cissus quadrangularis L. Extract Against Human Cervical Cancer Cells: In Vitro and In Silico Analysis

Background: Cervical cancer is the second leading cause of cancer in women, which necessitates safe and potential therapeutic agents. Objective: This study was designed to investigate the antiproliferative effect of ethanolic extract of Cissus quadrangularis L. (CQ) against human cervical adenocarcinoma HeLa cell line and in silico analysis of selected active agents against apoptosis executioner enzyme caspase-3. Methods: Cell viability was analyzed in HeLa cells at different concentrations (25-300 μg/ml) of CQ extract. Reactive oxygen species (ROS) generation, cellular apoptosis, cell cycle analysis and caspases-3 activation were evaluated. In silico structure-based virtual screening analysis was carried out using AutoDock Vina and iGEMDOCK. Results: Cell viability was analyzed in HeLa cells at different concentrations (25-300 μg/ml) of CQ extract. Reactive oxygen species (ROS) generation, cellular apoptosis, cell cycle analysis and caspases-3 activation were evaluated. In silico, structure-based virtual screening analysis was carried out using AutoDock Vina and iGEMDOCK. Results: Cell viability of HeLa cells was reduced significantly (p < 0.05) in a dose-dependent manner, however, CQ extract showed non-toxic to normal kidney epithelial NRK-52E cells. CQ extract induced the intracellular ROS level, nuclear condensation and reduced the mitochondrial membrane potential (MMP) with the induction of annexin V-FITC positive cells. CQ extract arrested cells in G0/G1 and G2/M checkpoints and activated caspase-3 activity significantly in HeLa cells. The molecular docking study showed a strong binding affinity of CQ phytocomponents against the caspase-3 (PDB ID: 1GFW) protein of human apoptosis. PASS analyses of selected active components using Lipinski’s Rule of five showed promising results. Further, drug-likeness and toxicity assessment using OSIRIS Data Warrior V5.2.1 software exhibited the feasibility of phytocomponents as drug candidates with no predicted toxicity. Conclusion: This study suggested that active constituents in CQ extract can be considered as potential chemotherapeutic candidates in the management of cervical cancer.

Drug Repositioning for Ovarian Cancer Treatment: An Update

Abstract:Ovarian cancer (OC) is one of the most prevalent malignancies in female reproductive organs, and its 5-year survival is below 45%. Despite the advances in surgical and chemotherapeutic options, OC treatment is still a challenge, and new anticancer agents are urgently needed. Drug repositioning has gained significant attention in drug discovery, representing a smart way to identify new clinical applications for drugs whose human safety and pharmacokinetics have already been established, with great time and cost savings in pharmaceutical development endeavors. This review offers an update on the most promising drugs repurposable for OC treatment and/or prevention.

Human Papillomavirus E7 Oncoprotein Promotes Proliferation and Migration through the Transcription Factor E2F1 in Cervical Cancer Cells

Background: High-Risk Human Papillomavirus (HR-HPV) persistent infection is the main cause of cervical cancer and its precancerous lesions. A previous study showed that HPV16 and HPV58 infections were the most common infection types in the local region. Some studies also declared that HPV58 E7 variants increased the risk of cervical cancer among Asian populations. Objective: This study aimed to determine whether the HPV58 E7 T20I (C632T) variant promotes the malignant behavior of cervical cancer cells and the underlying mechanism of the HR-HPV E7 oncoprotein involved in the development of cervical cancer. Methods: CCK-8 and clone formation assays were used to detect cell proliferation ability. Transwell assays and cell wound healing assays were used to evaluate cell migration ability. Targeted knockdown of E2F1 expression using specific siRNA, RT-qPCR and Western blot were performed to assess gene expression changes. A chromatin immunoprecipitation assay was used to verify that E2F1 interacted with the TOP2A promoter region. Results: HPV58 E7 and HPV58 E7M oncoproteins increased the proliferation and migration ability of cervical cancer cells. However, the HPV58 E7 T20I variant did not promote malignant behaviors compared with wildtype HPV58 E7. HPV E7 and E7M oncoproteins increased the expression of TOP2A, BIRC5 and E2F1, and knockdown of HPV E7 decreased their expression. Low E2F1 expression reduced the expression of TOP2A and BIRC5 and inhibited the proliferation and migration ability of cervical cancer cells. E2F1 interacted with the TOP2A gene promoter region to promote its transcriptional expression. Conclusions: The HPV58 E7 T20I variant did not promote malignant behaviors compared with wild-type HPV58 E7. The HR-HPV E7 oncoprotein enhanced the proliferation and migration of cervical cancer cells, which was considered to be due to the HPV E7 oncoprotein, increasing the expression of BIRC5 and TOP2A by upregulating the transcription factor E2F1.

Acyl Urea Compounds Therapeutics and its Inhibition for Cancers in Women: A Review

Acyl urea compounds have garnered significant attention in cancer therapeutics, particularly for their potential effectiveness against cancers that predominantly affect women, such as breast and ovarian cancers. The paper presents a report on the investigation of acyl urea compounds that are reported to involve a multi-faceted approach, including synthetic chemistry, biological assays, and computational modeling. A wealth of information on acyl urea and its purported effects on cancer affecting women has been gathered from different sources and condensed to provide readers with a broad understanding of the role of acyl urea in combating cancer. Acylureas demonstrate promising results by selectively inhibiting key molecular targets associated with cancer progressions, such as EGFR, ALK, HER2, and the Wnt/β-catenin signaling pathway. Specifically, targeting acyl ureas impedes tumor proliferation and metastasis while minimizing harm to healthy tissues, offering a targeted therapeutic approach with reduced side effects compared to conventional chemotherapy. Continued research and clinical trials are imperative to optimize the efficacy and safety profiles of acylurea-based therapies and broaden their applicability across various cancer types. Acyl urea compounds represent a promising class of therapeutics for the treatment of cancers in women, particularly due to their ability to selectively inhibit key molecular targets involved in tumor growth and progression. The combination of synthetic optimization, biological evaluation, and computational modeling has facilitated the identification of several lead compounds with significant anticancer potential. This abstract explores the therapeutic mechanisms and targeted pathways of acyl ureas in combating these malignancies, which will be useful for future studies.

Chrysin Exhibits Selective Antiproliferative and Antimigratory Activities in a Wide Range of Human-derived Cervical Cancer Cell Lines

Background: In the past few years, the antiproliferative activities of chrysin (5,7-dihydroxyflavone) have garnered significant attention in anticancer drug discovery due to its promising ability to suppress cancer cell proliferation. However, studies on its effects on cervical cancer are limited and have primarily focused on HeLa cells. Objective: In order to better understand its therapeutic potential for cervical cancer, we assessed the antiproliferative and anti-migratory effects of chrysin in a wide range of human-derived cell lines comprising C33A (human papillomavirus/HPV-negative), HeLa (HPV 18-positive), SiHa (HPV 16-positive), and CaSKi (HPV 16 and 18- positive), in comparison to a human epithelial cell line derived from spontaneously immortalized cell, HaCaT. Methods: Cell viability was determined using the MTT assay, while the clonogenic assay evaluated long-term cytotoxicity. Morphological alterations were observed via light microscopy, and cell death was assessed using Annexin V FITC/propidium iodide (PI) staining. Total reactive oxygen species (ROS) levels were measured by fluorescence microscopy, the mitochondrial transmembrane potential was assessed using TMRE, and lipid peroxidation was analyzed using DPPP. Additionally, wound healing migration and cell invasion assays were conducted. Results: Chrysin selectively inhibited cell proliferation and induced apoptosis in every cervical cancer cell line assessed while exerting minimal effects on HaCaT cells. Additionally, it triggered mitochondrial redox imbalance and significantly suppressed both migration and invasion of cervical cancer cells. Conclusion: Based on these results, chrysin appears to be a promising candidate as an anticancer agent for both HPV-associated and HPV-independent cervical cancers, emphasizing the necessity for further exploration in subsequent studies.

Cervical Cancer Therapeutics: An In-depth Significance of Herbal and Chemical Approaches of Nanoparticles

Abstract: Cervical cancer emerges as a prominent health issue, demanding attention on a global level for women's well-being, which frequently calls for more specialized and efficient treatment alternatives. Traditional therapies may have limited tumour targeting and adverse side effects. Recent breakthroughs have induced a transformative shift in the strategies employed against cervical cancer. biocompatible herbal nanoparticles and metallic particles made of gold, silver, and iron have become promising friends in the effort to fight against this serious disease and understand the possibility of these nanoparticles for targeted medication administration. this review article delves into the latest advancements in cervical cancer research. The safety and fabrication of these nanomaterials and their remarkable efficacy against cervical tumour spots are addressed. This review study, in short, provides an extensive introduction to the fascinating field of metallic and herbal nanoparticles in cervical cancer treatment. The information that has been examined points to a bright future in which women with cervical cancer may experience fewer side effects, more effective therapy, and an improved quality of life. This review holds promise and has the potential to fundamentally reshape the future of cervical cancer treatment by addressing urgent issues and unmet needs in the field.

Design, Synthesis, and In vitro Anti-cervical Cancer Activity of a Novel MDM2-p53 Inhibitor Based on a Chalcone Scaffold

Objective: Several novel fluorinated chalcone derivatives were synthesized, and their in vitro anticervical cancer activity and mechanism of action were investigated using the parent nucleus of licorice chalcone as the lead compound backbone and MDM2-p53 as the target. Methods: In this study, 16 novel chalcone derivatives (3a–3r) were designed and synthesized by molecular docking technology based on the licorice chalcone parent nucleus as the lead compound scaffold and the cancer apoptosis regulatory target MDM2–p53. The structures of these compounds were confirmed by 1H-NMR, 13C-NMR, and HR-ESI-MS. The inhibitory effects of the compounds on the proliferation of three human cervical cancer cell lines (SiHa, HeLa, and C-33A) and two normal cell lines (H8 and HaCaT) were determined by MTT assay, and the initialstructure–activity relationship was analyzed. Transwell and flow cytometry were used to evaluate the effects of target compounds on the inhibition of cancer cell migration and invasion, apoptosis induction, and cell cycle arrest. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to detect the effects of candidate compounds on mRNA, p53, and Murine double minute 2 (MDM2) protein expression. The binding characteristics of the target compounds to the MDM2 protein target in the p53–MDM2 pathway were evaluated by molecular docking technology. Results: The target compounds had considerable inhibitory activity on the proliferation of three cervical cancer cell lines. Among them, compound 3k (E)-3-(4-(dimethylamino)phenyl)-2-methyl-1-(3-(trifluoromethyl)phenyl) prop-2-en-1-one) showed the highest activity against HeLa cells (IC50=1.08 μmol/L), which was better than that of the lead compound Licochalcone B, and 3k showed lower toxicity to both normal cells. Compound 3k strongly inhibited the migration and invasion of HeLa cells and induced apoptosis and cell cycle arrest at the G0/G1 phase. Furthermore, compound 3k upregulated the expression of p53 and BAX and downregulated the expression of MDM2, MDMX, and BCL2. Moreover, molecular docking results showed that compound 3k could effectively bind to the MDM2 protein (binding energy: −9.0 kcal/mol). These results suggest that the compounds may activate the p53 signaling pathway by inhibiting MDM2 protein, which prevents cancer cell proliferation, migration, and invasion and induces apoptosis and cell cycle arrest in cancer cells. Conclusion: This study provides a new effective and low-toxicity drug candidate from licochalcone derivatives for treating cervical cancer.

Gemini Curcumin Suppresses Proliferation of Ovarian Cancer OVCAR-3 Cells via Induction of Apoptosis

Background: Ovarian cancer has the highest mortality rate among gynecological malignancies. Despite recent advances in treatment, most patients still suffer from poor prognosis. Curcumin has shown highly cytotoxic effects against different types of cancer. However, its poor bioavailability restricts its clinical application. Gemini Curcumin (GeminiCur) has been developed to overcome this limitation. Objective: Here, we aimed to unravel the inhibitory effect of Gemini-Cur in ovarian cancer. Methods: OVCAR-3 cells were treated with free curcumin and Gemni-Cur in a time- and dose-dependent manner. Then, the anticancer activity was investigated by uptake kinetics, cellular viability and apoptotic assays. Furthermore, we evaluated the BAX/Bcl-2 expression ratio by real-time PCR and western blotting. Results: Our data showed that gemini surfactant nanoparticles enhance the cellular uptake of curcumin compared to free curcumin (p<0.01). Regarding the growth inhibitory effect of nano-curcumin, the results demonstrated that Gemini-Cur suppresses the proliferation of OVCAR-3 cells through induction of apoptosis (p<0.001). Conclusion: The results illustrate that Gemini-Cur nanoparticles have a great potential for developing novel therapeutics against ovarian cancer.

The Antitumor Efficiency of Zinc Finger Nuclease Combined with Cisplatin and Trichostatin A in Cervical Cancer Cells

Background: Persistent infection with the high-risk of human papillomavirus (HR-HPVs) is the primary etiological factor of cervical cancer; HR-HPVs express oncoproteins E6 and E7, both of which play key roles in the progression of cervical carcinogenesis. Zinc Finger Nucleases (ZFNs) targeting HPV E7 induce specific shear of the E7 gene, weakening the malignant biological effects, hence showing great potential for clinical transformation. Objective: Our aim was to develop a new comprehensive therapy for better clinical application of ZFNs. We here explored the anti-cancer efficiency of HPV targeted ZFNs combined with a platinum-based antineoplastic drug Cisplatin (DDP) and an HDAC inhibitor Trichostatin A (TSA). Methods: SiHa and HeLa cells were exposed to different concentrations of DDP and TSA; the appropriate concentrations for the following experiments were screened according to cell apoptosis. Then cells were grouped for combined or separate treatments; apoptosis, cell viability and proliferation ability were measured by flow cytometry detection, CCK-8 assays and colony formation assays. The xenograft experiments were also performed to determine the anti-cancer effects of the combined therapy. In addition, the HPV E7 and RB1 expressions were measured by western blot analysis. Results: Results showed that the combined therapy induced about two times more apoptosis than that of ZFNs alone in SiHa and HeLa cells, and much more inhibition of cell viability than either of the separate treatment. The colony formation ability was inhibited more than 80% by the co-treatment, the protein expression of HPV16/18E7 was down regulated and that of RB1 was elevated. In addition, the xenografts experiment showed a synergistic effect between DDP and TSA together with ZFNs. Conclusion: Our results demonstrated that ZFNs combined with DDP or TSA functioned effectively in cervical cancer cells, and it provided novel ideas for the prevention and treatment of HPV-related cervical malignancies.

Beta-Caryophyllene Suppresses Ovarian Cancer Proliferation by Inducing Cell Cycle Arrest and Apoptosis

Background: Ovarian cancer is the fifth most common cause of cancer deaths among women with lesser prognostics. Current treatment options are chemotherapy with platinum and taxane based chemotherapy. β-Caryophyllene (BCP) an essential oil found in many plant species is known to possess an anti-proliferative effect. Objective: We aimed to investigate the antiproliferative, cytotoxic, and apoptotic role of BCP against ovarian cancer cells PA-1 and OAW 42. Methods: The antiproliferative effect of BCP was determined by MTT assay and cell viability by trypan blue exclusion assay. Cell cycle and live/dead cell analyses were performed by flow cytometry to determine cell cycle distribution and apoptosis, respectively. Results: Results of MTT assay proved the anti-proliferative effect of BCP in a dose and time-dependent manner in ovarian cancer cells. Cell cycle analysis showed that BCP induced S Phase arrest in OAW 42 cells. Results of apoptosis assay confirmed the apoptosis inducing potential of BCP in ovarian cancer cells. The apoptosis is mediated by caspase-3 activation and PARP cleavage. Conclusion: The results of our present study prove that BCP exerts its action partly by inducing cell cycle arrest and apoptosis in ovarian cancer. We conclude that BCP is a potential anti-cancer agent.