Department of Bioscience Technology, College of Science, Chung Yuan Christian University, Zhongli district, Taoyuan, Taiwan.
Department of Radiology, Taoyuan General Hospital, Taoyuan district, Taoyuan, Taiwan.
PLoS One. 2018 Oct 11;13(10):e0205249. doi: 10.1371/journal.pone.0205249. eCollection 2018.
Exposure to 3,5-dimethylaminophenol (3,5-DMAP), the metabolite of the 3-5-dimethylaniline, was shown to cause high levels of oxidative stress in different cells. The aim of the present work was to observe whether this metabolite can lead to cytotoxicity, oxidative stress, DNA damage and cell cycle changes in non-small cell lung cancer A549 cells. 3,5-DMAP caused a dose-dependent increase in cytotoxicity, generation of superoxide (O2-.), inductions in the enzyme activities orchestrating cellular antioxidant balance, increases in lipid peroxidation as well as DNA damage. However, 3,5-DMAP showed significantly lower cytotoxicity towards human lung fibroblast (HLF) cells. 3,5-DMAP also led to molecular events, like inducing apoptotic markers (ie. p53, Bad, Bax and cytochrome c); decreasing anti-apoptotic proteins (Bcl-2) and alterations in cell cycle. Our findings indicate that the cytotoxicity caused by this particular alkylaniline metabolite led to initiation of caspase 3-mediated apoptosis. Furthermore, 3,5-DMAP attenuated carcinogenic properties like migration capacity of A549 cells and eventually inhibited growth of A549 cells in an in vivo mouse model. Tumor sections showed that 3,5-DMAP down-regulated c-Myc expression but up-regulated p53 and cytochrome c, all of which might result in tumor growth arrest. Co-treatment with N-acetylcysteine provided reductions in cytotoxicity and positively modulated genetic events induced by 3,5-DMAP in A549 cells. In conclusion, our findings demonstrate 3,5-DMAP may be a potential anti-cancer drug in cancer, due to its self redox cycling properties.
暴露于 3,5-二甲基氨基酚（3,5-DMAP），即 3,5-二甲基苯胺的代谢物，已被证明会导致不同细胞中高水平的氧化应激。本研究旨在观察该代谢物是否会导致非小细胞肺癌 A549 细胞的细胞毒性、氧化应激、DNA 损伤和细胞周期改变。3,5-DMAP 导致细胞毒性呈剂量依赖性增加，超氧化物（O2-）生成增加，协调细胞抗氧化平衡的酶活性诱导，脂质过氧化增加以及 DNA 损伤增加。然而，3,5-DMAP 对人肺成纤维细胞（HLF）的细胞毒性明显较低。3,5-DMAP 还导致了分子事件，如诱导凋亡标志物（即 p53、Bad、Bax 和细胞色素 c）；降低抗凋亡蛋白（Bcl-2）并改变细胞周期。我们的研究结果表明，这种特定的烷基亚硝胺代谢物引起的细胞毒性导致 caspase 3 介导的细胞凋亡的启动。此外，3,5-DMAP 减弱了 A549 细胞的致癌特性，如迁移能力，最终在体内小鼠模型中抑制了 A549 细胞的生长。肿瘤切片显示，3,5-DMAP 下调了 c-Myc 的表达，但上调了 p53 和细胞色素 c，所有这些都可能导致肿瘤生长停滞。与 N-乙酰半胱氨酸联合治疗可降低细胞毒性并正向调节 3,5-DMAP 在 A549 细胞中诱导的遗传事件。总之，我们的研究结果表明，由于 3,5-DMAP 具有自身的氧化还原循环特性，它可能是一种有潜力的抗癌药物。
