Rafoxanide promotes apoptosis and autophagy of gastric cancer cells by suppressing PI3K /Akt/mTOR pathway
Rafoxanide promotes apoptosis and autophagy of gastric cancer cells by suppressing PI3K /Akt/mTOR pathway
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拉福尼特通过抑制PI3K/Akt/mTOR通路促进胃癌细胞凋亡和自噬
DOI：
10.1016/j.yexcr.2019.111691
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发表时间：
2019-12-15
影响因子：
3.7
通讯作者：
Xue, Wan-Jiang
中科院分区：
文献类型：
--
作者：
Liu, Jia-Zhou;Hu, Yi-Lin;Xue, Wan-Jiang
雷福尼特是兽药中常用的抗蠕虫药物，是水杨酰苯胺类的主要化合物。此前的研究报道，雷复尼特作为BRAF V600 E突变蛋白的抑制剂，可以抑制结直肠癌、多发性骨髓瘤和皮肤癌的生长。然而，其对胃癌的治疗作用及其可能的机制尚未被研究。在此，我们发现雷复尼特在体外抑制GC细胞的增殖，将细胞周期阻滞在G 0/G1期，并促进GC细胞的凋亡和自噬。用特异性自噬抑制剂3-甲基腺嘌呤治疗通过抑制自噬向凋亡的转换而显著抑制凋亡细胞死亡效应。从机制上讲，我们发现雷复尼特通过抑制PI 3 K/Akt/mTOR信号通路的活性来抑制体外GC细胞的生长。该过程诱导自噬，其基本上导致GC细胞的凋亡。裸鼠皮下移植瘤模型的结果也表明，雷复尼特在体内抑制GC细胞的生长。综上所述，我们的研究结果表明，雷复尼特在体外和体内都抑制GC细胞的生长，这表明了一种潜在的治疗GC的候选药物。
Rafoxanide is commonly used as anti-helminthic medicine in veterinary medicine, a main compound of salicylanilide. Previous studies have reported that rafoxanide, as an inhibitor of BRAF V600E mutant protein, inhibits the growth of colorectal cancer, multiple myeloma, and skin cancer. However, its therapeutic effect on gastric cancer (GC) and the potential mechanism has not been investigated. Here, we have found that rafoxanide inhibited the proliferation of GC cells in vitro, arrested the cell cycle in the G0/G1 phase, and promoted apoptosis and autophagy in GC cells. Treatment with specific autophagy inhibitor 3-methyladenine drastically inhibited the apoptotic cell death effect by suppressing the switch from autophagy to apoptosis. Mechanistically, we found that rafoxanide inhibited the growth of GC cells in vitro by inhibiting the activity of the PI3K/Akt/mTOR signaling pathway. This process induced autophagy, which essentially resulted in the apoptosis of GC cells. Results from subcutaneous implanted tumor models in nude mice also indicated that rafoxanide inhibited the growth of GC cells in vivo. Taken together, our findings revealed that rafoxanide inhibited the growth of GC cells both in vitro and vivo, indicating a potential drug candidate for the treatment of GC.