Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells
Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells
复制标题
醉茄素 A 与奥沙利铂联合的协同抗肿瘤活性可触发人胰腺癌细胞中活性氧介导的 PI3K/AKT 通路失活
DOI：
10.1016/j.canlet.2014.11.026
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发表时间：
2015-02-01
期刊：
影响因子：
9.7
通讯作者：
Qin, Renyi
中科院分区：
文献类型：
--
作者：
Li, Xu;Zhu, Feng;Qin, Renyi
由于奥沙利铂的毒副作用和耐药，其在胰腺癌治疗中的应用受到了限制。我们研究了从药用植物Withania somnifera中分离的生物活性成分withaferin A （WA）与奥沙利铂在体外和体内对人PC的协同作用。我们发现，WA通过线粒体功能障碍和PI3K/AICT通路失活的机制显著增强奥沙利铂诱导的PC细胞生长抑制和凋亡。联合处理导致细胞内活性氧（ROS）显著积累。用ROS清除剂n -乙酰半胱氨酸预处理细胞完全阻断联合处理诱导的细胞凋亡，恢复AKT失活的表达，揭示了ROS在细胞凋亡和AKT调控中的重要作用。在体内，联合治疗的抗肿瘤效果较单药最强，且无明显的附加毒性。这些结果支持奥沙利铂和WA联合治疗可以促进PC治疗有效策略的发展。2014爱思唯尔爱尔兰有限公司版权所有。
Application of oxaliplatin for the treatment of pancreatic cancer (PC) is restricted owing to its toxic side effects and drug resistance. We investigated how withaferin A (WA), a bioactive component isolated from the medicinal plant Withania somnifera, acts synergistically with oxaliplatin on human PC in vitro and in vivo. We found that WA enhanced oxaliplatin-induced growth suppression and apoptosis in PC cells dramatically through a mechanism involving mitochondrial dysfunction and inactivation of the PI3K/AICT pathway. Combination treatment resulted in significant accumulation of intracellular reactive oxygen species (ROS). Pretreatment of cells with the ROS scavenger N-acetylcysteine completely blocked the apoptosis induced by combination treatment, and recovered expression of AKT inactivation, which revealed the important role of ROS in apoptosis and AKT regulation. In vivo, combination therapy showed the strongest anti-tumor effects compared with single agents, without obvious additional toxicity. These results support the notion that combination treatment with oxaliplatin and WA could facilitate development of an effective strategy for PC treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.