Wang Chien-Hao, Baskaran Rathinasamy, Ng Shawn Shang-Chuan, Wang Tso-Fu, Li Chi-Cheng, Ho Tsung-Jung, Hsieh Dennis Jine-Yuan, Kuo Chia-Hua, Chen Ming-Cheng, Huang Chih-Yang
Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan.
Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
J Cancer. 2023 Jan 22;14(3):393-402. doi: 10.7150/jca.77322. eCollection 2023.
Oxaliplatin-based therapy is used as a first-line drug to treat metastatic colorectal cancer. However, long-term and repeated drug treatment resulted in drug resistance and the failure of chemotherapy. Various natural compounds were previously reported to act as chemosensitizers to reverse drug resistance. In this study, we found that platycodin D (PD), a saponin found in , inhibited LoVo and OR-LoVo cells proliferation, invasion, and migration ability. Our results indicated that combined treatment of oxaliplatin with PD dramatically reduced the cellular proliferation in both LoVo and OR-LoVo cells. Furthermore, treatment with PD dose-dependently decreased LATS2/YAP1 hippo signaling and survival marker p-AKT expression, as well as increased cyclin-dependent kinase inhibitor proteins such as p21 and p27 expression. Importantly, PD activates and promotes YAP1 degradation through the ubiquitination and proteasome pathway. The nuclear transactivation of YAP was significantly reduced under PD treatment, leading to transcriptional inhibition of the downstream genes regulating cell proliferation, pro-survival, and metastasis. In conclusion, our results showed that PD is suitable as a promising agent for overcoming oxaliplatin-resistant colorectal cancer.
基于奥沙利铂的疗法被用作治疗转移性结直肠癌的一线药物。然而，长期和重复的药物治疗导致了耐药性和化疗失败。先前有报道称，各种天然化合物可作为化学增敏剂来逆转耐药性。在本研究中，我们发现桔梗皂苷D（PD），一种存在于……中的皂苷，抑制了LoVo和OR-LoVo细胞的增殖、侵袭和迁移能力。我们的结果表明，奥沙利铂与PD联合治疗显著降低了LoVo和OR-LoVo细胞中的细胞增殖。此外，PD处理剂量依赖性地降低了LATS2/YAP1河马信号通路和存活标志物p-AKT的表达，同时增加了细胞周期蛋白依赖性激酶抑制剂蛋白如p21和p27的表达。重要的是，PD通过泛素化和蛋白酶体途径激活并促进YAP1的降解。在PD处理下，YAP的核转激活显著降低，导致对调节细胞增殖、促存活和转移的下游基因的转录抑制。总之，我们的结果表明，PD适合作为一种有前景的药物来克服奥沙利铂耐药的结直肠癌。
