Abstract
Ovarian cancer is a gynecologic malignancy with a high mortality rate. Eribulin, a non-taxane microtubule inhibitor approved for breast cancer and sarcoma, exerts antitumor efficacy in ovarian cancer cells (author et al, BPB. 2022:45). Ferroptosis, an iron-dependent cell death resulting from lipid peroxidation, is triggered by an accumulation of intracellular iron leading to oxidative stress. Reactive oxygen species (ROS) are a cause of oxidative stress, and crucial for mitochondrial homeostasis. We explored the involvement of ferroptosis and its mechanism in the antitumor activity of eribulin in ovarian cancer cells (RMG-1). Eribulin-induced cell death was mitigated by deferoxamine, an iron chelator. Eribulin elevated the levels of intracellular iron, lipid peroxides, ROS, and mitochondrial membrane potential. Eribulin downregulated NRF2, heme oxygenase-1 (HO-1) and dihydroorotate dehydrogenase (DHODH), whereas glutathione peroxidase (GPX4) protein level remained unaffected. Combining eribulin with ML210, a GPX4-inhibiting ferroptosis inducer, enhanced eribulin-induced cell death. Taken together, eribulin triggers ferroptosis characterized by increased intracellular iron, lipid peroxidation, and ROS in ovarian cancer cells. The ferroptosis-inducing effect may be orchestrated through suppression of the NRF2/HO-1 signaling pathway and lipid peroxidation inhibition by DHODH. These findings illuminate the potential of eribulin-induced ferroptosis as a therapeutic strategy in ovarian cancer treatment.
