Endocrine, Metabolic & Immune Disorders - Drug Targets

Intervening Stemness and Angiogenesis in Cervical Carcinoma: Revisiting the Efficacy of Natural Compounds

Inhibiting TLR9 Signaling Stimulates Apoptosis and Cell Cycle Arrest, and Alleviates Angiogenic Property in Human Cervical Cancer Cells

Aims: The aim of the study was to assess the effect of blocking TLR9 signaling on the proliferation of cervical cancer cells and its angiogenic property. Background: Toll-Like Receptors (TLRs) have been implicated for their crucial role in not only cervical cancer but also in other malignancies. TLR9 is expressed on an array of cells such as macrophages, dendritic cells, melanocytes, and keratinocytes and is reported to modulate oncogenesis along with tumorigenesis by augmenting NF-κB mediated inflammation within the tumor environment. TLR9 has also been reported to positively regulate oncogenesis within the cervix and as a marker to evaluate malignant remodeling of cervical squamous cells. Therefore, this study was designed to explore the functional relevance of blocking the TLR9signaling pathway in cervical cancer cells. Objective: The objective of the current study was to investigate the effect of human TLR9 antagonist, ODN INH-18, on apoptosis and cell cycle regulation, and angiogenic property of human cervical cancer Caski cells. Method: MTT assay was performed to measure cell viability and flow cytometry analysis was performed to assess cell cycle arrest. Quantitative Real-Time PCR (qRT-PCR) analysis was performed to measure fold change in the gene expression of various markers of apoptosis, cell cycle regulation, and angiogenesis. Result: The qRT-PCR results showed a higher expression level of TLR9 mRNA in Caski cervical cancer cells as compared to normal cervical keratinocytes. The apoptotic, angiogenic, and cell cycle regulatory factors were also deregulated in Caski cells in comparison to normal keratinocytes. The MTT assay demonstrated that treatment of TLR9 antagonist, ODN INH18, significantly reduced the proliferation of Caski cells in a dose-dependent manner. Treatment of ODN INH18 led to substantial cell cycle arrest in Caski cells at G0/G1 phase. Moreover, the qRT-PCR results demonstrated that ODN INH18 treatment led to suppressed mRNA expression of Bcl-2 and enhanced expression of Bax, signifying the induction of apoptosis in Caski cells. Moreover, the expression of cyclin D1, Cdk4, and Cdc25A was found to be reduced whereas expression of p27 was increased in ODN INH18-treated Caski cells; indicating G0/G1 phase arrest. Interestingly, expression of VEGF and VCAM-1 was found to be significantly inhibited in ODN INH18-treated Caski cells, substantiating alleviation of angiogenic property of cervical cancer cells. Conclusion: The results of our study suggest that inhibiting TLR9 signaling might be an interesting therapeutic intervention for the treatment of cervical cancer.

Anti-Cancerous Effect of Rutin Against HPV-C33A Cervical Cancer Cells via G0/G1 Cell Cycle Arrest and Apoptotic Induction

Background: Nowadays, the potential therapeutic role of various bioflavonoids including Curcumin, Luteolin and Resveratrol has currently been well-documented in a vast range of fatal complications including synaptic failure and cancers. These bioflavonoids are widely being implemented for the treatment of various cancers as they possess anti-cancerous, anti-oxidant and anti-inflammatory properties. Moreover, they are also used as a better alternative to conventional therapies since; these are non-toxic to cells and having no or least side effects. Notably, the pertinent therapeutic role of Rutin in cervical cancer is still unsettled however, its anti-cancerous role has already been reported in other cancers including prostate and colon cancer. Rutin (Vitamin P or Rutoside) is a polyphenolics flavonoid exhibiting multi-beneficial roles against several carcinomas. Objective: Despite the evidence for its several biological activities, the anticancer effects of Rutin on human cervical cancer (C33A) cells remain to be explored. In this study, the anticancer potential of Rutin was investigated by employing the key biomarkers such as nuclear condensation reactive oxygen species (ROS), apoptosis, and changes in mitochondrial membrane potential (MMP). Results: Our findings showed that Rutin treatment reduced the cell viability, induced significant increase in ROS production and nuclear condensation in dose-dependent manner. Moreover, Rutin provoked apoptosis by inducing decrease in MMP and activation of caspase-3. Cell cycle analysis further confirmed the efficacy of Rutin by showing cell cycle arrest at G0/G1 phase. Conclusion: Thus, our study is envisaged to open up interests for elucidating Rutin as an anticancerous agent against cervical cancer.

Anticancer Potential of Quercetin, Epigallocatechin Gallate, Kaempferol, Apigenin, and Curcumin against Several Human Carcinomas

Cancer remains a global health problem that requires constant research for the development of new treatment strategies. Flavonoids, a diverse group of naturally occurring polyphenolic compounds abundant in fruits, vegetables, and other plant sources, have received considerable attention for their potential anticancer properties. This review aimed to provide a comprehensive overview of the current scientific literature onfive specific natural flavonoids, namely quercetin, Epigallocatechin Gallate (EGCG), kaempferol, apigenin, andcurcumin that have been widely reported in numerous carcinomas and evaluate their effectiveness and mechanisms in fighting different types of cancer. Knownfor its antioxidant and anti-inflammatory properties, quercetin has shown promise in inhibiting cancer cells and modulating key signaling pathways. EGCG, a prominent catechin found in green tea, has beenextensively studied for its ability to induce apoptosis and inhibit angiogenesis, highlighting its potential as an anticancer agent. Kaempferol has antioxidant and anti-inflammatory effects and has shown anticancer potential by modulating cellular processes involved in tumor development. Apigenin, abundant in parsley and chamomile, has been shown to exert anticancer properties by interrupting the cell cycle and inducing apoptosis in cancer cells. Curcumin has shown several anticancer effects, including inhibiting cell proliferation, inducing apoptosis, and modulating inflammatory pathways. Despite these promising findings, it is essential to recognize the complexity of cancer biology and theneed for further research to clarify the precise mechanisms of action of these natural flavonoids and optimize their therapeutic applications. Furthermore, understanding flavonoids' potential synergy and interactions with traditional cancer therapies is paramount for developing effective combinatorial strategies. This review thus aimed to summarize the current knowledge onthese natural flavonoids and provide insight into their potential role as an adjunctive or stand-alone therapy in the fight against breast, prostate, colon, lung, skin, ovarian, liver, and pancreatic cancer.

The Impact of Polycystic Ovary Syndrome (PCOS) on the Risk of Developing Ovarian Cancer and Thyroid Disorders: A Comprehensive Review

Abstract: Polycystic ovary syndrome (PCOS) is a common hormonal disorder that affects women. It is characterized by hyperandrogenism, polycystic ovarian morphology, and other related disorders. It is associated with various health conditions, such as infertility and increased risk of heart problems. Ovarian cancer is also a significant concern, as it is the fifth leading cause of death in women. While there is evidence suggesting a potential association between PCOS and ovarian cancer, the exact nature of this relationship remains unclear. Thyroid disorders, particularly hypothyroidism and Hashimoto's thyroiditis, have also been linked to PCOS. The presence of hypothyroidism can contribute to the development of polycystic ovarian morphology, affecting ovulation and hormone balance. Many works have shown a higher ubiquity of autoimmune thyroid disease in PCOS patients, indicating a potential association between the two conditions. The occurrence of PCOS, hirsutism, and acne underscores the frequency of endocrine disorders in women. This review paper examines the present relevant work on the association between PCOS and ovarian cancer as well as PCOS and thyroid disorders. A systematic literature search was conducted on the internet, such as PubMed, Scopus, and Google Scholar database, to identify peer-reviewed publications pertaining to PCOS, ovarian cancer, and thyroid disorders. While some studies have delineated a significant link between PCOS and ovarian cancer or thyroid disorders, others have yielded inconclusive results. Further research is necessary to establish a definitive causal relationship between these conditions. Understanding the relationship between PCOS, ovarian cancer, and thyroid disorders is crucial for early detection, accurate diagnosis, and effective management of these conditions. Identifying potential risk factors and developing appropriate screening strategies can improve women's health outcomes and reduce the burden associated with these disorders.

In silico Identification of MHC Displayed Tumor Associated Peptides in Ovarian Cancer for Multi-Epitope Vaccine Construct

Background: Recognizing the potential of the immune system, immunotherapies have brought about a revolution in the treatment of cancer. Low tumour mutational burden and strong immunosuppression in the peritoneal tumor microenvironment (TME) lead to poor outcomes of immune checkpoint inhibition (ICI) and CART cell therapy in ovarian cancer. Alternative immunotherapeutic strategies are of utmost importance to achieve sound clinical success. Introduction: The development of peptide vaccines based on tumor-associated antigens (TAAs) for ovarian cancer cells can be a potential target to provoke an anti-tumor immune response and subsequent clearance of tumour cells. The purpose of this in-silico study was to find potential epitopes for a multi-epitope vaccine construct using the immunopeptidomics landscape of ovarian carcinoma. Methods: The four TAAs (MUC16, IDO1, FOLR1, and DDX5) were selected for potential epitopes prediction. The epitopes for B-cells, helper T-lymphocytes (HTL), and Cytotoxic Tlymphocytes (CTL) were predicted on the basis of antigenic, allergenic, and toxic properties. These epitopes were combined with suitable linkers and an adjuvant to form a multi-epitope construct. Results: Four HTLs, 13 CTLs, and 6 potential B-cell epitopes were selected from the predicted epitope. The designed multi-epitope construct was potentially immunogenic, non-toxic, and non-allergenic. Physicochemical properties and higher-order structural analyses of the final construct revealed a potential vaccine candidate. Conclusion: The designed vaccine construct has the potential to trigger both humoral and cellular immune responses and may be employed as a therapeutic immunization candidate for ovarian malignancies. However, further in vitro and animal experimentation is required to establish the efficacy of the vaccine candidate.