A Platinum(IV)-Ursolic Acid Conjugate Overcomes Cisplatin Resistance in Ovarian Cancer by Targeting XPO1 and PARP1

Abstract Cisplatin is a cornerstone chemotherapeutic for ovarian cancer, yet its clinical utility is constrained by severe systemic toxicity and acquired drug resistance. Here we report a novel platinum (IV) prodrug, US-CIS-OH, generated by conjugating cisplatin with ursolic acid (UA), a natural pentacyclic triterpenoid with intrinsic anticancer activity. US-CIS-OH, markedly increases platinum uptake and DNA platination in cisplatin-resistant ovarian cancer cells, induces S- and G2/M-phase arrest and apoptosis, and suppresses cell migration and clonogenic growth. Chemoproteomic profiling indicates that US-CIS-OH directly engages the XPO1 and PARP1, and is associated with increased levels of cleaved caspase-3. In a cisplatin-resistant ovarian cancer xenograft model, US-CIS−OH elicits marked tumor regression with minimal toxicity. This dual-acting system achieves synergistic effects from both the intact conjugated and bioreductively released cisplatin. Collectively, these results identify US-CIS−OH as a promising next-generation platinum-based agent to overcome cisplatin resistance by enhancing DNA damage, promoting apoptosis, and limiting metastatic traits.