Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma
Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma
复制标题
三氧化二砷联合PX-478有效治疗胰腺导管腺癌
DOI：
10.1016/j.canlet.2016.05.016
复制
发表时间：
2016-08-10
期刊：
影响因子：
9.7
通讯作者：
Ren, He
中科院分区：
文献类型：
--
作者：
Lang, Mingxiao;Wang, Xiuchao;Ren, He
三氧化二砷（ATO）不仅被认为是治疗白血病的一种有前景的药物，而且也被认为是治疗实体肿瘤的一种有前景的药物。以往的研究表明，ATO的细胞毒性主要依赖于活性氧的诱导。然而，ATO在胰腺导管腺癌中仅取得了适度的作用，这表明现有的自由基清除蛋白，如缺氧诱导因子-1，减弱了这种作用。本研究的目的是探讨ATO与缺氧诱导因子-1抑制剂PX-478联合治疗的效果及其潜在机制。我们在体外实验中发现，PX-478能显著增强ATO对Panc-1和BxPC-3胰腺癌细胞的抗生长和促凋亡作用。同时，在体内小鼠异种移植模型中，ATO与PX-478的协同作用也优于任何单一药物。进一步研究表明，ATO + PX-478的抗肿瘤作用来源于活性氧诱导的细胞凋亡。接下来，我们证实了缺氧诱导因子-1通过其下游靶标叉头盒O转录因子清除活性氧，这一作用可能证明ATO加PX-478治疗胰腺癌的策略是正确的。(C) 2016由爱思唯尔爱尔兰有限公司出版。
Arsenic trioxide (ATO) has been selected as a promising treatment not only in leukemia but also in solid tumors. Previous studies showed that the cytotoxicity of ATO mainly depends on the induction of reactive oxygen species. However, ATO has only achieved a modest effect in pancreatic ductal adenocarcinoma, suggesting that the existing radical scavenging proteins, such as hypoxia inducible factor-1, attenuate the effect. The goal of this study is to investigate the effect of combination treatment of ATO plus PX-478 (hypoxia-inducible factor-1 inhibitor) and its underlying mechanism. Here, we showed that PX-478 robustly strengthened the anti-growth and pro-apoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro. Meanwhile, in vivo mouse xenograft models also showed the synergistic effect of ATO plus PX-478 compared with any single agent. Further studies showed that the anti-tumor effect of ATO plus PX-478 was derived from the reactive oxygen species-induced apoptosis. We next confirmed that Hypoxia-inducible factor-1 cleared reactive oxygen species by its downstream target, forkhead box O transcription factors, and this effect may justify the strategy of ATO plus PX-478 in the treatment of pancreatic cancer. (C) 2016 Published by Elsevier Ireland Ltd.