A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells
A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells
复制标题
新型 STAT3 抑制剂 HO-3867 通过活性氧依赖性内质网应激诱导人胰腺癌细胞凋亡
DOI：
10.1097/cad.0000000000000470
复制
发表时间：
2017-04-01
影响因子：
2.3
通讯作者：
Liang, Guang
中科院分区：
文献类型：
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作者：
Hu, Yan;Zhao, Chengguang;Liang, Guang
胰腺癌是实体瘤中最常见的恶性肿瘤，并呈逐年上升趋势。因此，迫切需要发现新的抗癌药物来治疗胰腺癌。近年来，有报道称化合物HO-3867是天然产物姜黄素的新型类似物，具有低毒、抗肿瘤活性。然而，这种化合物攻击癌细胞的潜在机制尚不清楚。本研究发现HO-3867在2μmol/l浓度下对PANC-1和BXPC-3细胞表现出良好的抗肿瘤活性。重要的是，还发现 HO-3867 处理显着诱导人胰腺癌细胞系中活性氧 (ROS) 的产生，从而诱导 PANC-1 和 BXPC-3 细胞。与 ROS 清除剂 N-乙酰半胱氨酸共同治疗，部分消除了 HO-3867 诱导的细胞凋亡。丝裂原激活蛋白激酶的激活和内质网应激表明 ROS 生成在介导 HO-3867 抗癌作用中的下游事件。此外，在 HO-3867 诱导的细胞凋亡中观察到了与 ROS 途径无关的直接 STAT3 抑制。综上所述，这项工作的结果表明，ROS 依赖性 ER 应激和 STAT3 途径都与新型化合物 HO-3867 诱导的细胞凋亡有关。
Pancreatic cancer is the most commonly diagnosed malignancy among solid tumors and has shown an increasing trend year by year. Thus, there is an urgent need for the discovery of new anticancer drugs for the treatment of pancreatic cancer. In recent years, it has been reported that the compound HO-3867, a novel analog of the natural product curcumin, showed antitumor activity with low toxicity. However, the underlying mechanism of this compound’s attack on cancer cells is not very clear. In the present study, it was found that HO-3867 showed good antitumor activity at the concentration of 2 &mgr;mol/l in PANC-1 and BXPC-3 cells. Importantly, it was also found that HO-3867 treatment significantly induced reactive oxygen species (ROS) production in human pancreatic cancer cell lines, inducing PANC-1 and BXPC-3 cells. Co-treatment with the ROS scavenger, N-acetyl cysteine, partially abrogated HO-3867-induced cell apoptosis. The activation of mitogen-activated protein kinase and endoplasmic reticulum stress indicated a downstream event of ROS generation in mediating the anticancer effect of the HO-3867. In addition, independent of the ROS pathway, direct STAT3 inhibition was observed in HO-3867-induced cell apoptosis. Taken together, the results of this work suggest that both the ROS-dependent ER stress and STAT3 pathways were implicated in the cell apoptosis induced by the novel compound HO-3867.