Abstract

Ovarian cancer exhibits the highest mortality rate among all gynecologic malignancies. A major obstacle in its clinical management is the development of chemoresistance. Consequently, there is an urgent and unmet need to develop novel therapeutic agents specifically targeting drug-resistant forms of ovarian cancer. In this study, we investigated the antitumor activity and potential mechanisms of a novel nitric oxide (NO) donor, 3A72, in a P-glycoprotein (P-gp) overexpressed drug-resistant ovarian cancer model. In vitro experiments revealed that 3A72 exerts robust cytotoxic effects, with a clear dose-dependent inhibition of DNA synthesis. Mechanistically, 3A72 generates high concentrations of NO within both the cytoplasm and lysosomes. This NO release promotes dual modes of action: first, it destabilizes lysosomal membranes, triggering the leakage of sequestered iron and subsequent Fenton reaction-driven oxidative stress; second, NO-mediated oxidative damage induces mitochondrial dysfunction and depletes intracellular glutathione (GSH). Together, these effects impair the SLC7A11-GPX4 antioxidant axis, ultimately enhancing ferroptosis in drug-resistant ovarian cancer cells. Furthermore, administration of 3A72 markedly suppressed tumor growth in a subcutaneous xenograft mouse model bearing OVCAR8/ADR cells, with no apparent signs of systemic toxicity observed, demonstrating a favorable biosafety profile. Collectively, this study provides preliminary yet compelling evidence for the potent antiproliferative effects of 3A72 against drug-resistant ovarian cancer cells, along with mechanistic insights into its mode of action. These findings highlight the therapeutic promise of 3A72 as a novel candidate for the treatment of chemoresistant ovarian tumors.