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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-defcient saos2 osteosarcoma cancer cells).VCA-1-induced apoptosis was found to be mainly via the extrinsic apoptosis pathway involving caspase-8 activation and XlAP reduction.Forced over-expression of XlAP 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 XlAP reduction,suggesting that XlAP reduction may be resulted from oxidative stress.In conclusion,data from this study reveal the essential roles of ROS generation and XlAP reduction in VCA-1-induced apoptosis in cancer cells.VCA-1 may be a novel cancer therapeutic agent,especially in p53-mutant human cancers.