The protective effect of silibinin against mitomycin C-induced intrinsic apoptosis in human melanoma A375-S2 cells.
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.
Jiang
Yuan-yuan
YY
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, China.
Wang
Hong-jun
HJ
Wang
Jing
J
Tashiro
Shin-ichi
S
Onodera
Satoshi
S
Ikejima
Takashi
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005562:Formazans / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D016685:Mitomycin / Q000494:pharmacology*; D015394:Molecular Structure; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D005562:Formazans; D012838:Silymarin; D013778:Tetrazolium Salts; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C079782:MTT formazan; D000077385:Silybin; D016685:Mitomycin; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D053453:Caspase 9; C447939:SIRT1 protein, human; D056564:Sirtuin 1