Phenylarsine oxide (PAO) induces apoptosis in HepG2 cells via ROS-mediated mitochondria and ER-stress dependent signaling pathways,Metallomics

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Phenylarsine oxide (PAO) induces apoptosis in HepG2 cells via ROS-mediated mitochondria and ER-stress dependent signaling pathways
Metallomics ( IF 2.9 ) Pub Date : 2017-08-03 00:00:00 , DOI: 10.1039/c7mt00179g
Ping Huang _{1,

2,

3,

4} , Yu Hua Zhang _{4,

5,

6} , Xiao Wei Zheng _{1,

2,

3,

4} , Yu Jia Liu _{1,

2,

3,

4} , Hong Zhang _{1,

2,

3,

4} , Luo Fang _{1,

2,

3,

4} , Yi Wen Zhang _{1,

2,

3,

4} , Chang Yang _{3,

4,

7,

8,

9} , Khairul Islam _{3,

4,

9,

10,

11} , Chao Wang _{3,

4,

9,

10,

11} , Hua Naranmandura _{3,

4,

7,

8,

9}

Affiliation

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.

中文翻译：

苯氧化砷（PAO）通过ROS介导的线粒体和ER应激依赖性信号传导途径诱导HepG2细胞凋亡

三氧化二砷（As ₂ O ₃）是一种旧药，最近已重新引入作为急性早幼粒细胞白血病（APL）的治疗剂。尽管As ₂ O ₃也被用于体外和体内治疗其他类型的癌症，但据报道，在临床试验中，单一药物As ₂ O ₃对非血液系统恶性肿瘤的疗效较差。最近，一些报道表明，有机砷化合物可以替代As ₂ O ₃的处理方法。耐药性癌症。在这项研究中，我们旨在研究有机砷化合物苯氧化砷（PAO）对人肝细胞癌（HCC）HepG2细胞是否具有有效的细胞毒性作用。我们的结果表明，PAO不仅对HepG2细胞的增殖具有有效的抑制作用，而且还以剂量和时间依赖性的方式激活了凋亡相关蛋白（例如caspase-3和-9和poly-ADP核糖聚合酶）。。此外，暴露于PAO后，细胞内ROS特异性地积累在线粒体和内质网（ER）中，这表明它们是PAO诱导的细胞毒性的靶细胞器。此外，当细胞用抗氧化剂N预处理时-乙酰半胱氨酸（NAC），细胞凋亡和内质网应激显着减弱，表明凋亡诱导和细胞死亡可能是通过ROS介导的线粒体和内质网应激依赖的信号传导途径发生的。

更新日期：2017-08-23

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