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Potential pharmacological properties of Lico B include anti\u2010inflammatory, anti\u2010bacterial, anti\u2010oxidant, and anti\u2010cancer activities. However, its biological effects on melanoma and squamous cell carcinoma (SCC) are unknown. Based on these known facts, this study investigated the role of Lico B in apoptosis, through the extrinsic and intrinsic pathways and additional regulation of specificity protein 1 in human skin cancer cell lines. Annexin V\/7\u2010aminoactinomycin D staining, western blot analysis, mitochondrial membrane potential assay, and an anchorage\u2010independent cell transformation assay demonstrated that Lico B treatment of human melanoma and SCC cells significantly inhibited cell proliferation and induced apoptotic cell death. More specifically, Lico B induced apoptosis through the regulation of specificity protein 1 and apoptosis\u2010related proteins including CCAAT\/enhancer\u2010binding protein homologous protein, death receptors, and poly (ADP\u2010ribose) polymerase. These results indicate that Lico B has apoptotic effect on A375 and A431 skin cancer cells, suggesting the potential value of Lico B for the treatment of human melanoma and SCC. 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