Sharad S Singhal

Enhancing carboplatin sensitivity in ovarian cancer cells by blocking the mercapturic acid pathway transporter

Abstract Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione–electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment.

RLIP depletion suppresses ovarian cancer growth and metastasis

Emerging trends and treatment strategies in ovarian cancer: A comprehensive review

Ovarian cancer (OC) is the eighth leading cause of cancer deaths in women globally, mainly originating from epithelial cells. It is further divided into type-I and type-II based on histology, molecular, clinical, and epidemiological characteristics. OC is commonly diagnosed in postmenopausal women, although this varies by ethnicity and genetics. Non-Hispanic white women have higher rates of OC, while African American women, despite lower incidence, are diagnosed at a younger median age. Family history and BReast CAncer gene 1&2 (BRCA1/BRCA2) mutations significantly correlate with a heightened risk of OC. Obesity, particularly from childhood, is associated with a higher risk of OC. Late menopause and smoking, are linked to a higher risk, especially for mucinous and possibly serous OC. Hormone-replacement-therapy, particularly with unopposed estrogen, also increases the risk of OC. Endometriosis raises the risk for specific subtypes like clear cell and endometrioid carcinoma. Women who have never given birth (null-parity) are at higher-risk for endometrioid and clear cell carcinoma. Surgical resection is crucial for reducing primary and local metastatic disease, involving inspection of the peritoneal cavity, cytology, lymph node removal, and biopsies. The success of surgery is limited by the visibility, extent, and tissue infiltration of the disease. The choice between neoadjuvant-chemotherapy and primary debulking surgery depends on patient health and tumor biology. Secondary cytoreductive surgery may be beneficial for platinum-sensitive recurrent OC. The use of PARP inhibitors and targeted therapies adds complexity to surgical decisions. Ongoing trials and new therapeutic strategies are expected to enhance the management and outcomes of OC.

Role of Immunotherapy in Ovarian Cancer: Advances, Challenges, and Future Perspectives

Ovarian cancer (OC) remains one of the most challenging gynecologic malignancies due to its late-stage diagnosis, high recurrence rates, and limited survival outcomes. Immunotherapy has emerged as a transformative approach in cancer treatment, leveraging the immune system to target tumor cells. This chapter provides a comprehensive overview of immunotherapy in OC, discussing its mechanisms, key strategies, and clinical advancements. Key areas include the role of immune checkpoint inhibitors (ICIs), adoptive cell therapies (ACT), cancer vaccines, and oncolytic viruses. Despite promising preclinical and clinical outcomes, significant challenges persist, including low immunogenicity, resistance mechanisms, and immune-related adverse events. Strategies to address these barriers, such as combination therapies, biomarker-guided approaches, and the integration of artificial intelligence (AI) for personalization, are discussed. Emerging directions, including next-generation immune checkpoint targets and innovations in epigenetic and metabolic reprogramming, are explored to envision the future of immunotherapy in OC. By addressing these challenges and leveraging innovative strategies, immunotherapy has the potential to redefine the therapeutic landscape, improving survival and quality of life for patients with OC.