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. 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.
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Authors | Chia-Hua Liang, Guey-Horng Wang, Tzung-Han Chou, Shih-Hao Wang, Rong-Jyh Lin, Leong-Perng Chan, Edmund Cheung So, Jyh-Horng Sheu |
Journal | Biochimica et biophysica acta
(Biochim Biophys Acta)
Vol. 1820
Issue 7
Pg. 1149-57
(Jul 2012)
ISSN: 0006-3002 [Print] Netherlands |
PMID | 22348919
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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