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

Abstract

We hypothesized that IFN-A would enhance the apoptotic activity of bortezomib on melanoma cells. Combined treatment with bortezomib and IFN-A 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-A 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-A act through the extrinsic pathway of apoptosis via FADD-induced caspase-8 activation to initiate cell death. Finally, bortezomib and IFN-A 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-A for malignant melanoma. [Cancer Res 2008;68(20):8351-60]

Type III Interferons IL-28 and IL-29: Novel Interferon Family Members with Therapeutic Potential in Cancer Therapy

“…Lesinski et al reported that co-treatment of F0-melanoma cells with proteasome inhibitor Bortezomib and type III IFN synergistically increased cell death, similar to the combination of IFN- and Bortezomib [67]. We also observed that the combination of 5-fluorouracil (5-FU) or cisplatin (CDDP) with type III IFN drastically inhibited cell growth of the esophageal carcinoma cell lines [56].…”

Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma

“…26 It has been suggested that rhIFNα 2 b plays important roles in antitumor and antiviral activity and regulation of the immune system. 3,[8][9][10][11][12][13][14][15][16] The mechanism of the antitumor effect is not completely clear yet. However, studies have suggested it might inhibit tumor growth in vivo through tumor cellgrowth inhibition, tumor-cell apoptosis, oncogene-expression restraint, immune-system regulation, and tumor-angiogenesis suppression.…”

“…[5][6][7] Some studies show that IFNα, including IFNα 2 b, is also capable of exerting antitumor effects against HCC, hairy cell leukemia, lymphoma, melanoma, and breast cancer. 3,[8][9][10][11][12][13][14][15][16] However, an extensive clinical trial of IFNα 2 b for HCC was delayed, due to the weak therapeutic effect based on conventional drug-delivery methods. In general, these methods cause rapid degradation of IFNα 2 b in the body and induce severe side effects, due to the systemic distribution of drugs in the body causing bone marrow suppressions and neurologic disorders.…”

Noxa/Bcl-2 Protein Interactions Contribute to Bortezomib Resistance in Human Lymphoid Cells

“…In addition, FADD (FAS-associated death domain protein) and caspase 8 have been shown to play a role during bortezomib-induced apoptosis in melanoma and renal cell carcinoma cells (67)(68)(69). To assess the role of the death receptor pathway in bortezomib-induced apoptosis in Jurkat cells, we examined the bortezomib sensitivity of a series of Jurkat variants deficient in components of one apoptotic pathway or the other.…”