IFN-α and Bortezomib Overcome Bcl-2 and Mcl-1 Overexpression in Melanoma Cells by Stimulating the Extrinsic Pathway of Apoptosis

摘要: We hypothesized that IFN-α would enhance the apoptotic activity of bortezomib on melanoma cells. Combined treatment with and induced synergistic apoptosis in other solid tumor cell lines. Apoptosis was associated processing procaspase-3, procaspase-7, procaspase-8, procaspase-9 cleavage Bid poly(ADP-ribose) polymerase. Bortezomib plus effective at inducing cells overexpressed Bcl-2 or Mcl-1, suggesting this combination can overcome mitochondrial pathways survival resistance to apoptosis. The proapoptotic effects were abrogated by a caspase-8 inhibitor, led increased association Fas FADD before onset death, significantly reduced transfected dominant-negative construct small interfering RNA targeting Fas. These data suggest act through extrinsic pathway via FADD-induced activation initiate death. Finally, displayed statistically significant antitumor compared either agent alone both B16 murine model athymic mice bearing human A375 xenografts. support future clinical development for malignant melanoma. [Cancer Res 2008;68(20):8351–60]