Lin Liubing, Wang Jian, Sheng Shun, Shen Yanting, Liu Xiaolin, Xu Rongzhong, Li Yong
Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
These authors contributed equally to this work.
Cancer Drug Resist. 2025 Aug 7;8:40. doi: 10.20517/cdr.2025.94. eCollection 2025.
Cisplatin serves as a primary chemotherapeutic agent in the treatment of gastric cancer (GC), but resistance to cisplatin-based chemotherapeutic regimens hampers its clinical application. Corosolic acid (CA), a natural triterpenoid, exhibits both anti-inflammatory and anti-cancer activities. However, the effect of CA on improving cisplatin resistance in GC remains unclear. The study primarily aimed to evaluate whether CA increases the therapeutic efficacy of cisplatin against GC and to reveal its underlying mechanism. Cisplatin and CA were used to treat GC cells or cisplatin-resistant AGS cells (AGS-CR), and then cell viability, apoptosis, and growth were assessed using Cell Counting Kit-8, TdT-mediated dUTP nick end labeling, and clone formation assays, respectively. Glutathione peroxidase 4 (Gpx4) expression was measured through quantitative real-time PCR and western blotting assays. CA treatment induced a dose-dependent reduction in GC cell viability. The combination of cisplatin and CA resulted in enhanced cytotoxicity and pro-apoptotic effects compared to treatment with cisplatin alone. The effect of CA as a chemosensitizer in GC cells was damaged by a ferroptosis inhibitor, suggesting that CA decreased cisplatin chemoresistance by accelerating cancer cell ferroptosis. CA triggered cell ferroptosis by repressing Gpx4 expression in GC cells. Furthermore, elevated Gpx4 expression was significantly associated with poorer overall and disease-free survival. CA has the potential to increase cisplatin chemosensitivity in GC, and Gpx4 may represent a promising therapeutic target for its treatment.
顺铂是治疗胃癌（GC）的主要化疗药物，但对基于顺铂的化疗方案产生耐药性阻碍了其临床应用。科罗索酸（CA）是一种天然三萜类化合物，具有抗炎和抗癌活性。然而，CA对改善GC中顺铂耐药性的作用仍不清楚。本研究主要旨在评估CA是否能提高顺铂对GC的治疗效果，并揭示其潜在机制。使用顺铂和CA处理GC细胞或顺铂耐药的AGS细胞（AGS-CR），然后分别使用细胞计数试剂盒-8、TdT介导的dUTP缺口末端标记和克隆形成试验评估细胞活力、凋亡和生长情况。通过定量实时PCR和蛋白质印迹分析测量谷胱甘肽过氧化物酶4（Gpx4）的表达。CA处理导致GC细胞活力呈剂量依赖性降低。与单独使用顺铂治疗相比，顺铂和CA联合使用导致细胞毒性增强和促凋亡作用增强。铁死亡抑制剂破坏了CA作为GC细胞化学增敏剂的作用，表明CA通过加速癌细胞铁死亡降低了顺铂耐药性。CA通过抑制GC细胞中Gpx4的表达触发细胞铁死亡。此外，Gpx4表达升高与较差的总生存期和无病生存期显著相关。CA有可能增加GC中顺铂的化学敏感性，Gpx4可能是其治疗的一个有前景的治疗靶点。
