Phenylarsine oxide (PAO) induces apoptosis in HepG2 cells via ROS-mediated mitochondria and ER-stress dependent signaling pathways
Phenylarsine oxide (PAO) induces apoptosis in HepG2 cells via ROS-mediated mitochondria and ER-stress dependent signaling pathways
复制标题
苯胂氧化物 (PAO) 通过 ROS 介导的线粒体和 ER 应激依赖性信号通路诱导 HepG2 细胞凋亡
DOI：
10.1039/c7mt00179g
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发表时间：
2017-12-01
期刊：
影响因子：
3.4
通讯作者：
Naranmandura, Hua
中科院分区：
文献类型：
--
作者：
Huang, Ping;Zhang, Yu Hua;Naranmandura, Hua
三氧化二砷（As 2 O3）是一种古老的药物，最近被重新引入作为急性早幼粒细胞白血病（APL）的治疗药物。虽然As 2 O3也被应用于治疗其他类型的癌症在体外和体内，据报道，单一的药物As 2 O3对非血液系统恶性肿瘤的疗效差，在临床试验。最近，一些报告表明，有机砷化合物可以作为治疗抗As 2 O3癌症的可能替代品。在这项研究中，我们的目的是探讨是否有机砷化合物氧化苯胂（PAO）对人肝细胞癌（HCC）HepG 2细胞具有强大的细胞毒作用。我们的研究结果表明，PAO不仅对HepG 2细胞的增殖具有有效的抑制作用，而且还激活了凋亡相关蛋白（例如，半胱天冬酶-3和-9和聚ADP核糖聚合酶）。此外，细胞内的活性氧在线粒体和内质网（ER）暴露于PAO后，具体积累，这意味着它们是PAO诱导的细胞毒性的靶细胞器。此外，当用抗氧化剂N-乙酰半胱氨酸（NAC）预处理细胞时，凋亡和ER-应激显著减弱，表明凋亡和细胞死亡的诱导可能通过ROS介导的线粒体和ER-应激依赖的信号通路发生。
Arsenic trioxide (As2O3) is an old drug that has recently been reintroduced as a therapeutic agent for acute promyelocytic leukemia (APL). Although As2O3 is also applied to treat other types of cancer in vitro and in vivo, it has been reported that single agent As2O3 has poor efficacy against non-hematologic malignant cancers in clinical trials. Recently, a few reports have indicated that organic arsenic compounds can be a possible alternative for the treatment of As2O3-resistant cancers. In this study, we aimed to investigate whether the organic arsenic compound phenylarsine oxide (PAO) has potent cytotoxic effects against human hepatocellular carcinoma (HCC) HepG2 cells. Our results showed that PAO not only had a potent inhibitory effect on the proliferation of HepG2 cells but also activated apoptosis-related proteins (e.g., caspase-3 and -9 and poly-ADP ribose polymerase) in a dose-and time-dependent manner. Furthermore, intracellular ROS were specifically accumulated in the mitochondria and endoplasmic reticulum (ER) after exposure to PAO, implying that they are the target organelles for PAO-induced cytotoxicity. Additionally, when the cells were pretreated with antioxidant N-acetylcysteine (NAC), apoptosis and ER-stress were attenuated significantly, suggesting that induction of apoptosis and cell death probably occurs through the ROS-mediated mitochondria and ER-stress dependent signaling pathways.