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

¹ Division of Hematology and Oncology, Department of Internal Medicine, ² Integrated Biomedical Sciences Graduate Program, ³ Department of Surgery, ⁴ The Center for Biostatistics, ⁵ Department of Pathology, and ⁶ Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio and ⁷ Archemix Corp., Cambridge, Massachusetts

Requests for reprints: William E. Carson III, Department of Surgery, The Ohio State University, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-6306; Fax: 614-293-3465; E-mail: william.carson{at}osumc.edu.

Key Words: IFN- • bortezomib • Velcade • proteasome inhibitor • melanoma • apoptosis

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

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