Sun Meng-Yao, Sun Jian, Tao Jie, Yuan Yu-Xia, Ni Zhen-Hua, Tang Qing-Feng
Department of Clinical Laboratory and Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
Department of Clinical Laboratory, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China.
Evid Based Complement Alternat Med. 2018 Dec 2;2018:4278568. doi: 10.1155/2018/4278568. eCollection 2018.
Gastric cancer (GC) is the third leading cause of cancer-related death. Chemotherapy resistance remains the major reason for GC treatment failure and poor overall survival of patients. Our previous studies have proved that Zuo Jin Wan (ZJW), a traditional Chinese medicine (TCM) formula, could significantly enhance the sensitivity of cisplatin (DDP)-resistant gastric cancer cells to DDP by inducing apoptosis via mitochondrial translocation of cofilin-1. However, the underlying mechanism remains poorly understood. This study aimed to evaluate the effects of ROCK/PTEN/PI3K on ZJW-induced apoptosis in vitro and in vivo. We found that ZJW could significantly activate the ROCK/PTEN pathway, inhibit PI3K/Akt, and promote the apoptosis of SGC-7901/DDP cells. Inhibition of ROCK obviously attenuated ZJW-induced apoptosis as well as cofilin-1 mitochondrial translocation, while inhibition of PI3K had the opposite effects. In vivo, combination treatment of DDP and ZJW (2000 mg/kg) significantly reduced tumor growth compared with DDP alone. Moreover, the combined administration of ZJW and DDP increased the expression of cleaved ROCK and p-PTEN while it decreased p-PI3K and p-cofilin-1, which was consistent with our in vitro results. These findings indicated that ZJW could effectively inhibit DDP resistance in GC by regulating ROCK/PTEN/PI3K signaling and provide a promising treatment strategy for gastric cancer.
胃癌（GC）是癌症相关死亡的第三大主要原因。化疗耐药仍然是GC治疗失败和患者总体生存率低的主要原因。我们之前的研究证明，中药方剂左金丸（ZJW）可通过诱导丝切蛋白-1的线粒体易位诱导凋亡，从而显著增强顺铂（DDP）耐药胃癌细胞对DDP的敏感性。然而，其潜在机制仍知之甚少。本研究旨在评估ROCK/PTEN/PI3K在体外和体内对ZJW诱导凋亡的影响。我们发现ZJW可显著激活ROCK/PTEN通路，抑制PI3K/Akt，并促进SGC-7901/DDP细胞凋亡。抑制ROCK明显减弱ZJW诱导的凋亡以及丝切蛋白-1的线粒体易位，而抑制PI3K则产生相反的效果。在体内，与单独使用DDP相比，DDP与ZJW（2000 mg/kg）联合治疗显著降低了肿瘤生长。此外，ZJW与DDP联合给药增加了裂解的ROCK和p-PTEN的表达，同时降低了p-PI3K和p-丝切蛋白-1的表达，这与我们的体外结果一致。这些发现表明，ZJW可通过调节ROCK/PTEN/PI3K信号有效抑制GC中的DDP耐药，并为胃癌提供一种有前景的治疗策略。
