5-epi-Sinuleptolide induces cell cycle arrest and apoptosis through tumor necrosis factor/mitochondria-mediated caspase signaling pathway in human skin cancer cells

Background: Skin cancers are reportedly increasing worldwide. Developing novel anti-skin cancer drugs with minimal side effects is necessary to address this public health issue. Sinuleptolide has been demonstrated to possess anti-cancer cell activities; however, the mechanisms underlying the anti-skin cancer effects of 5-epi-sinuleptolide and sinuleptolide remain poorly understood. Methods: Apoptosis cell, cell-cycle-related regulatory factors, and mitochondria- and death receptor-dependent caspase pathway in 5-epi-sinuleptolide-induced cell apoptosis were examined using SCC25 cells. Results: 5-epi-Sinuleptolide inhibited human skin cancer cell growth more than did sinuleptolide. Treatment of SCC25 cells with 5-epi-sinuleptolide increased apoptotic body formation, and induced cell-cycle arrest during the G(2)/M phase. Notably, 5-epi-sinuleptolide up-regulated p53 and p21 expression and inhibited G(2)/M phase regulators of cyclin B1 and cyclin-dependent kinease 1 (CDK1) in SCC25 cells. Additionally, 5-epi-sinuleptolide induced apoptosis by mitochondria-mediated cytochrome c and Bax up-expression, down-regulated Bcl-2, and activated caspase-9 and -3. 5-epi-Sinuleptolide also up-regulated tBid, which is associated with up-regulation of tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL) and their cognate receptors (i.e., TNF-R1, TNF-R2 and Fas), downstream adaptor TNF-R1-associated death domain (TRADD) and Fas-associated death domain (FADD), and activated caspase-8 in SCC25 cells. Conclusions: The analytical results indicate that the death receptor- and mitochondria-mediated caspase pathway is critical in 5-epi-sinuleptolide-induced apoptosis of skin cancer cells. General significance: This is the first report suggesting that the apoptosis mediates the anti-tumor effect of 5-epi-sinuleptolide. The results of this study might provide useful suggestions for designing of antitumor drugs for skin cancer patients. (C) 2012 Elsevier B.V. All rights reserved.