A Platinum(IV)-Ursolic Acid Conjugate Overcomes Cisplatin Resistance in Ovarian Cancer by Targeting XPO1 and PARP1
Ziqi Pan, Zhiying Qin, Ziyu Qian, Gui Han, Mengqi Sun, Yueying Bian, Tinghui Jin, Yuan Yin, Yongjie Zhang, Zhanbo Wang, Zhangjian Huang, Xijing Chen, Shentian Zhuang, Di ZhaoAbstract
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.