Inducing Alternative Forms of Cell Death in Multidrug Resistant Ovarian Cancer

Ovarian cancer remains the deadliest gynecological cancer for women today. In 2021, an estimated 21,410 new cases of ovarian cancer were diagnosed in the US, and approximately 13,770 of these women will not survive the disease[2]. This malignancy’s low survival rate is attributed to late diagnoses, as well as the cancer’s tendency to recur after chemotherapy treatment due to acquired drug resistance. The standard of care for this disease includes surgery and chemotherapy. One of the commonly used chemotherapeutic drugs is cisplatin, which works by inducing a programmed form of cell death known as apoptosis. However, many ovarian cancer tumors develop cisplatin drug resistance. Therefore, inducing alternate forms of cell death in these cancer cells is being considered for new treatment options. Erastin is a novel drug thought to induce ferroptosis, an iron-dependent method of cell death[6]. The objective of this research was to determine if erastin induced cellular death via ferroptosis in ovarian cancer cells, and further, if using erastin with cisplatin could sensitize cisplatin resistant cells to ferroptosis. The high grade serous ovarian carcinoma cell line, OVCAR-3, was used for this research. OVCAR-3 is a cisplastin drug resistant cell line that is often used as an in vitro model of HGSOC and was derived from a 60-year-old patient with metastatic cancer. Cells were treated with cisplatin, erastin, and in combination to test the drug’s efficacy at inducing cellular death. Ferredoxin, an agent that inhibits ferroptosis, was used as a control. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assays were used to determine the effects of different treatments on OVCAR-3 cells. Results from these experiments suggest that erastin is a potential therapeutic agent in the treatment of cisplatin drug resistant HGSOC. Using erastin in combination with cisplatin may improve patient outcomes, in addition to lowering the therapeutic dose of cisplatin in order to minimize adverse effects that are associated with this medication. Hence, ferroptosis is an alternative form of cell death for HGSOC that can be further exploited to develop innovative treatment regimens for patients with ovarian cancer. 2. American Cancer Society. Cancer Facts & Figures 2021. 2021 [cited 2021 November]. 6.Zhou, H.-H., et al., Erastin Reverses ABCB1-Mediated Docetaxel Resistance in Ovarian Cancer. Frontiers in oncology, 2019. 9: p. 1398-1398