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

AbstractBACKGROUND:
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.
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 anti-tumor drugs for skin cancer patients.
AuthorsChia-Hua Liang, Guey-Horng Wang, Tzung-Han Chou, Shih-Hao Wang, Rong-Jyh Lin, Leong-Perng Chan, Edmund Cheung So, Jyh-Horng Sheu
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1820 Issue 7 Pg. 1149-57 (Jul 2012) ISSN: 0006-3002 [Print] Netherlands
PMID22348919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • 5-episinuleptolide
  • Diterpenes
  • Fas Ligand Protein
  • RNA, Messenger
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha
  • Caspases
Topics
  • Apoptosis (drug effects)
  • Blotting, Western
  • Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
  • Caspases (metabolism)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Survival (drug effects)
  • Diterpenes (pharmacology)
  • Fas Ligand Protein (metabolism)
  • Fluorescent Antibody Technique
  • Humans
  • Mitochondria (drug effects)
  • RNA, Messenger (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (drug effects)
  • Skin Neoplasms (drug therapy, metabolism, pathology)
  • TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha (metabolism)

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