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.

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.

Jiang YY ，Huang H ，Wang HJ ，Wu D ，Yang R ，Tashiro S ，Onodera S ，Ikejima T ... -  《-》

Selective inhibition of SCLC growth by the A12 anti-IGF-1R monoclonal antibody correlates with inhibition of Akt.

Yeh J ，Litz J ，Hauck P ，Ludwig DL ，Krystal GW ... -  《LUNG CANCER》

Oridonin induces human melanoma A375-S2 cell death partially through inhibiting insulin-like growth factor 1 receptor signaling.

Wang HJ ，Li D ，Yang FY ，Tashiro S ，Onodera S ，Ikejima T ... -  《-》

Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the panc

Nair PN ，De Armond DT ，Adamo ML ，Strodel WE ，Freeman JW ... -  《ONCOGENE》

Insulin-like growth factor-1 receptor acts as a growth regulator in synovial sarcoma.

Friedrichs N ，Küchler J ，Endl E ，Koch A ，Czerwitzki J ，Wurst P ，Metzger D ，Schulte JH ，Holst MI ，Heukamp LC ，Larsson O ，Tanaka S ，Kawai A ，Wardelmann E ，Buettner R ，Pietsch T ，Hartmann W ... -  《-》