title: Interruption of mitochondrial complex IV activity and cytochrome c expression activated O₂·⁻-mediated cell survival in silibinin-treated human melanoma A375-S2 cells via IGF-1R-PI3K-Akt and IGF-1R-PLC γ-PKC pathways.
abstract: Silibinin was reported to have high cyto-toxicity in many malignant cell lines, however, it showed low cyto-toxicity in treatment of human melanoma A375-S2 cells and even protected these cells against certain stress insults. Reactive oxygen species was reported to have controversial effects on cancer chemotherapy. In this study we investigated the mechanism of reactive oxygen species generation and the role of reactive oxygen species in protecting cells against silibinin induced cyto-toxicity in A375-S2 cells. We found that silibinin induced the generation of large amount of superoxide anion (O(2)(∙-)) and small amount of hydrogen peroxide (H(2)O(2)) through down-regulating the activity of mitochondrial complex IV and the protein level of cytochrome c. We also discovered that O(2)(∙-) generation activated insulin like growth factor-1 receptor (IGF-1R) and its down-stream phosphatidylinositol 3-kinases-Akt (PI3K-Akt) and phospholipase C γ-protein kinase C (PLC γ-PKC) signaling pathways, which were augmented by H(2)O(2) scavenger catalase. Scavenging O(2)(∙-) by superoxide dismutase (SOD) or inhibition of IGF-1R-PI3K-Akt and IGF-1R-PLC γ-PKC signaling pathways increased cell apoptosis. Therefore, O(2)(∙-) mediated cell resistance to silibinin via activating IGF-1R-PI3K-Akt and IGF-1R-PLC γ-PKC pathways in silibinin treated A375-S2 cells.
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, PR China. emma_840101@yahoo.com.cn
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Jiang
authors.forename: Huai
authors.initials: H
authors.lastname: Huang
authors.forename: Hong-jun
authors.initials: HJ
authors.lastname: Wang
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Ri
authors.initials: R
authors.lastname: Yang
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Onodera
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikejima
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008545:Melanoma / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D012838:Silymarin; D013481:Superoxides; D000077385:Silybin; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D051966:Phospholipase C gamma