Augmenting Chemotherapy Response in Ovarian Cancer: N-3 Polyunsaturated Fatty Acids Target TOP2A

Introduction: Ovarian cancer, a significant contributor to global female mortality and the third most prevalent gynecological cancer in India, poses challenges for conventional treatments like chemotherapy and radiotherapy. Method: This study explores the effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on the efficacy of chemotherapy, particularly doxorubicin (DOXO), in ovarian teratocarcinoma (PA-1) cells. Rigorous cell viability assays demonstrated that n-3 PUFAs in combination significantly enhanced DOXO-induced cytotoxicity, reducing cell survival and migration potential. N-3 PUFAs and DOXO synergistically reduced colony formation in the group receiving the combination treatment as seen in the clonogenic assays, as further validated by hanging drop and apoptosis assays results. Results: Network pharmacological investigations pinpointed the gene topoisomerase II A (TOP2A) as a pivotal target, while molecular docking simulations revealed structural similarities between n-3 PUFAs (DHA or EPA) and DOXO, implying probable common mechanisms such as DNA intercalation and topoisomerase II inhibition. Molecular dynamics simulations delineated distinct interaction profiles for Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) with TOP2A, offering mechanistic insights. Combining computational and experimental methodologies reveals the synergistic benefits of n-3 PUFAs and DOXO in treating ovarian cancer, leading to improved therapeutic outcomes. Conclusion: These results provide a comprehensive view of the potential of combining n-3 PUFAs with DOXO for more potent ovarian cancer treatments.