Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 668, Issue 1-2, Pages 78-87Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2011.06.007
Keywords
Silibinin; Superoxide anion; Hydrogen peroxide; Mitochondrial complex IV; Cytochrome c; IGF-1R; A375-S2 cell
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Funding
- National Key Scientific Project for New Drug Discovery and Development, P. R. China [2009ZX09301-012]
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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 (H2O2) 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 gamma-protein kinase C (PLC gamma-PKC) signaling pathways, which were augmented by H2O2 scavenger catalase. Scavenging O-2(.-) by superoxide dismutase (SOD) or inhibition of IGF-1R-PI3K-Akt and IGF-1R-PLC gamma-PKC signaling pathways increased cell apoptosis. Therefore, O-2(.-) mediated cell resistance to silibinin via activating IGF-1R-PI3K-Akt and IGF-1R-PLC gamma-PKC pathways in silibinin treated A375-S2 cells. Crown Copyright (C) 2011 Published by Elsevier B. V. All rights reserved.
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