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Varacin-1, a novel analog of varacin C, induces p53- independent apoptosis in cancer cells through ROS-mediated reduction of XIAP

Authors: Jing Zhou1, Wen-li Li2, Zi-xuan Wang3,4, Nai-yuan Chen4, Yue Tang3,4, Xiao-xiao Hu3,4, Jing-huan Deng4, Yixin Lu5, Guo-dong Lu3,4,6
1 Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
2 Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 511430, China
3 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China
4 Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
5 Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
6 Key Laboratory of High-incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education of China, Nanning 530021, China
Correspondence to: Guo-dong Lu: golden_lu@hotmail.com,
DOI: 10.1038/s41401-018-0005-y
Received: 13 October 2017
Accepted: 16 January 2018
Advance online: 17 May 2018

Abstract

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.
Keywords: varacin-1; apoptosis; p53; XIAP; ROS

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