Zhou Xiao-Hong, You Wei, Gu Han, Gao Fan, Shao Qi, Chen Guang, Xia Lei, Shen Aizong, Tang Liqin, Nie Xuan, You Ye-Zi
Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China.
J Med Chem. 2025 Jul 10;68(13):13455-13470. doi: 10.1021/acs.jmedchem.5c00086. Epub 2025 Jun 17.
Platinum-based antitumor drugs face significant challenges due to drug resistance, driven by reduced drug uptake, increased efflux, and apoptosis pathway inactivation. Overcoming platinum resistance holds paramount importance. Herein, we utilized docosahexaenoic acid as axial ligands to synthesize two Pt prodrugs, Pt-DHA and Pt-BisDHA, and explored their potentials to overcome drug resistance. Pt-DHA exhibited extremely potent antitumor efficacy, outperforming both Pt-BisDHA and cisplatin. Notably, unlike other platinum drugs, Pt-DHA uniquely accumulates more in cisplatin-resistant cells than in parental sensitive cells. Additionally, experimental results show that Pt-DHA induces notable ferroptosis in tumor cells even at very low concentrations, thereby highly augmenting its cytotoxicity against resistant cells. This dual capability, preferential accumulation in resistant cells and ferroptosis activation, enables Pt-DHA to reverse platinum resistance and effectively. This work provides a typical instance of developing platinum drugs with special mechanisms of action to overcome drug resistance.
基于铂的抗肿瘤药物由于耐药性而面临重大挑战，耐药性是由药物摄取减少、外排增加和凋亡途径失活所驱动的。克服铂耐药性至关重要。在此，我们利用二十二碳六烯酸作为轴向配体合成了两种铂前药，Pt-DHA和Pt-BisDHA，并探索了它们克服耐药性的潜力。Pt-DHA表现出极强的抗肿瘤功效，优于Pt-BisDHA和顺铂。值得注意的是，与其他铂类药物不同，Pt-DHA在顺铂耐药细胞中的积累比在亲本敏感细胞中更多。此外，实验结果表明，即使在非常低的浓度下，Pt-DHA也能在肿瘤细胞中诱导显著的铁死亡，从而大大增强其对耐药细胞的细胞毒性。这种双重能力，即在耐药细胞中的优先积累和铁死亡激活，使Pt-DHA能够有效逆转铂耐药性。这项工作提供了一个开发具有特殊作用机制的铂类药物以克服耐药性的典型实例。
