Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, China.
Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China.
Acta Pharmacol Sin. 2019 Feb;40(2):222-230. doi: 10.1038/s41401-018-0005-y. Epub 2018 May 17.
Varacin C is a promising anticancer agent and possesses acid-promoted and photo-induced DNA-damaging activities. In this study, we synthesized an analog varacin-1 (VCA-1) and examined its anticancer potentials. The results demonstrated that VCA-1 caused dose-dependent apoptotic cell death in cancer cells. Note that this action is independent of p53 status, because VCA-1 induced similar levels of apoptosis in two different panels of cell lines (HCT116 p53- wild-type vs. HCT116 p53-knockout colon cancer cells, and p53-expressing U2OS vs. p53-deficient saos2 osteosarcoma cancer cells). VCA-1-induced apoptosis was found to be mainly via the extrinsic apoptosis pathway involving caspase-8 activation and XIAP reduction. Forced over-expression of XIAP markedly prevented apoptosis, indicating its essential role in VCA-1 induced apoptosis. On the other hand, VCA-1 treatment enhanced intracellular ROS (reactive oxygen species) generation also in a p53-independent manner, and consequently promoted caspase activation. Pretreatment of N-acetyl cysteine (an antioxidant), rather than z-VAD (specific caspase inhibitor), markedly prevented XIAP reduction, suggesting that XIAP reduction may be resulted from oxidative stress. In conclusion, data from this study reveal the essential roles of ROS generation and XIAP reduction in VCA-1-induced apoptosis in cancer cells. VCA-1 may be a novel cancer therapeutic agent, especially in p53-mutant human cancers.
瓦拉辛 C 是一种很有前途的抗癌药物，具有酸促进和光诱导的 DNA 损伤活性。在这项研究中，我们合成了一种类似物瓦拉辛-1（VCA-1），并研究了其抗癌潜力。结果表明，VCA-1 可引起癌细胞中剂量依赖性的凋亡性细胞死亡。需要注意的是，这种作用独立于 p53 状态，因为 VCA-1 在两种不同的细胞系（HCT116 p53-野生型与 HCT116 p53-敲除结肠癌，以及 p53 表达的 U2OS 与 p53 缺失的 saos2 骨肉瘤）中诱导的凋亡水平相似。VCA-1 诱导的凋亡主要通过涉及半胱天冬酶-8 激活和 XIAP 减少的外在凋亡途径。强制过表达 XIAP 明显阻止了凋亡，表明其在 VCA-1 诱导的凋亡中起关键作用。另一方面，VCA-1 处理以 p53 非依赖性的方式增强了细胞内 ROS（活性氧）的产生，进而促进了半胱天冬酶的激活。用 N-乙酰半胱氨酸（抗氧化剂）预处理，而不是 z-VAD（特异性半胱天冬酶抑制剂）预处理，明显阻止了 XIAP 的减少，表明 XIAP 的减少可能是由于氧化应激。总之，本研究的数据揭示了 ROS 生成和 XIAP 减少在 VCA-1 诱导癌细胞凋亡中的重要作用。VCA-1 可能是一种新型的癌症治疗药物，尤其是在 p53 突变的人类癌症中。
