The protective effect of silibinin against mitomycin C-induced intrinsic apoptosis in human melanoma A375-S2 cells.

Abstract

Silibinin is known for its hepatoprotective, anti-inflammatory, and anti-carcinogenic effects. We found that silibinin exhibited a protective effect against chemotherapeutic reagent mitomycin C-induced cell death in A375-S2 cells in a p53-dependent manner, which contradicted the findings of previous studies investigating the anti-neoplastic activity of silibinin and developing silibinin as a potential anti-neoplastic drug in clinical therapy. Mitomycin C administration triggered a time- and dose-dependent cell death in A375-S2 cells. Apoptotic morphology, DNA fragmentation, and caspase-3 activation demonstrated that the major cause of A375-S2 cell death by mitomycin C was apoptosis. This was associated with a marked increase of p53 level and changes in mitochondria associated proteins. However, preincubation with silibinin prior to mitomycin C treatment substantially suppressed cell apoptosis, attenuated the change of p53 and Bcl-2 expressions, blocked the translocation of Bax to mitochondrial outer membrane, and ameliorated the loss of mitochondrial membrane potential, but mitomycin C stimuli led to few changes in the protein levels of caspase 8, Fas ligand, and Fas-associated death domain protein, indicating that silibinin protected cells from mitomycin C-induced apoptosis mainly via suppressing the mitochondria-mediated intrinsic apoptosis pathway, but not in an extrinsic manner.

• Authors: Yuan-yuan Jiang, Hong-jun Wang, Jing Wang, Shin-ichi Tashiro, Satoshi Onodera, Takashi Ikejima
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 111 Issue 2 Pg. 137-46 (Oct 2009) ISSN: 1347-8648 [Electronic] Japan
• PMID: 19834285 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antineoplastic
• Formazans
• Silymarin
• Tetrazolium Salts
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• MTT formazan
• Silybin
• Mitomycin
• L-Lactate Dehydrogenase
• Caspase 3
• Caspase 9
• SIRT1 protein, human
• Sirtuin 1

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects, physiology)
• Caspase 3 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cytoprotection (drug effects)
• DNA Fragmentation (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects)
• Formazans (metabolism)
• Humans
• L-Lactate Dehydrogenase (analysis, metabolism)
• Melanoma (genetics, metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (genetics, metabolism)
• Mitomycin (pharmacology)
• Molecular Structure
• Silybin
• Silymarin (chemistry, pharmacology)
• Sirtuin 1 (genetics, metabolism)
• Tetrazolium Salts (metabolism)
• Time Factors
• Tumor Suppressor Protein p53 (antagonists & inhibitors)
• bcl-2-Associated X Protein (genetics, metabolism)