BH3 Mimetic ABT-737 and a Proteasome Inhibitor Synergistically Kill Melanomas through Noxa-Dependent Apoptosis

• Published in: Journal of investigative dermatology Vol. 129; no. 4; pp. 964 - 971
• Main Authors: Miller, Leslie A., Goldstein, Nathaniel B., Johannes, Widya U., Walton, Christine H., Fujita, Mayumi, Norris, David A., Shellman, Yiqun G.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2009; Nature Publishing Group; Elsevier Limited
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biphenyl Compounds - pharmacology; Caspases - physiology; Cell Line, Tumor; Cysteine Proteinase Inhibitors - pharmacology; Dermatology; Drug Synergism; Humans; Leupeptins - pharmacology; Medical sciences; Melanoma - drug therapy; Melanoma - pathology; Mitochondria - physiology; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols - pharmacology; Piperazines - pharmacology; Proteasome Inhibitors; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-bcl-2 - physiology; Sulfonamides - pharmacology; Tumors of the skin and soft tissue. Premalignant lesions; Dermatology; Cell death; Proteasome inhibitor; Malignant melanoma; Malignant tumor; Cancer; Apoptosis
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2008.327

The Bcl-2 family is important in modulating sensitivity to anticancer drugs in many cancers, including melanomas. The BH3 mimetic ABT-737 is a potent small molecule inhibitor of the anti-apoptotic proteins Bcl-2/Bcl-XL/Bcl-w. In this report, we examined whether ABT-737 is effective in killing melanoma cells in combination with the proteasome inhibitor MG-132, and further evaluated the mechanisms of action. Viability, morphological, and Annexin V apoptosis assays showed that ABT-737 alone exhibited little cytotoxicity, yet it displayed strong synergistic lethality when combined with MG-132. In addition, the detection of Bax/Bak activation indicated that the combination treatment synergistically induced mitochondria-mediated apoptosis. Furthermore, mechanistic analysis revealed that this combination treatment induced expression of the pro-apoptotic protein Noxa- and caspase-dependent degradation of the anti-apoptotic protein, Mcl-1. Finally, siRNA-mediated inhibition of Mcl-1 expression significantly increased sensitivity to ABT-737 in these cells, and knocking down Noxa expression protected the cells from cytotoxicity induced by the combination treatment. These findings demonstrate that ABT-737 combined with MG-132 synergistically induced Noxa-dependent mitochondrial-mediated apoptosis. In summary, this study indicates promising therapeutic potential of targeting anti-apoptotic Bcl-2 family members in treating melanoma, and it validates rational molecular approaches that target anti-apoptotic defenses when developing cancer treatments.