title: 5-epi-Sinuleptolide induces cell cycle arrest and apoptosis through tumor necrosis factor/mitochondria-mediated caspase signaling pathway in human skin cancer cells.
abstract: 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 G2/M phase. Notably, 5-epi-sinuleptolide up-regulated p53 and p21 expression and inhibited G2/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-α (TNF-α) and Fas ligand (FasL) and their cognate receptors (i.e., TNF-RI, 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.
  
  
  CONCLUSIONS
  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 anti-tumor drugs for skin cancer patients.
authors.affiliation: Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. tinna_ling@mail.chna.edu.tw
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Liang
authors.forename: Guey-Horng
authors.initials: GH
authors.lastname: Wang
authors.forename: Tzung-Han
authors.initials: TH
authors.lastname: Chou
authors.forename: Shih-Hao
authors.initials: SH
authors.lastname: Wang
authors.forename: Rong-Jyh
authors.initials: RJ
authors.lastname: Lin
authors.forename: Leong-Perng
authors.initials: LP
authors.lastname: Chan
authors.forename: Edmund Cheung
authors.initials: EC
authors.lastname: So
authors.forename: Jyh-Horng
authors.initials: JH
authors.lastname: Sheu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C520059:5-episinuleptolide; D004224:Diterpenes; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases