Abstract |
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-X(L)/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.
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Authors | Leslie A Miller, Nathaniel B Goldstein, Widya U Johannes, Christine H Walton, Mayumi Fujita, David A Norris, Yiqun G Shellman |
Journal | The Journal of investigative dermatology
(J Invest Dermatol)
Vol. 129
Issue 4
Pg. 964-71
(Apr 2009)
ISSN: 1523-1747 [Electronic] United States |
PMID | 18987671
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- ABT-737
- Antineoplastic Agents
- Biphenyl Compounds
- Cysteine Proteinase Inhibitors
- Leupeptins
- Myeloid Cell Leukemia Sequence 1 Protein
- Nitrophenols
- PMAIP1 protein, human
- Piperazines
- Proteasome Inhibitors
- Proto-Oncogene Proteins c-bcl-2
- Sulfonamides
- Caspases
- benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Biphenyl Compounds
(pharmacology)
- Caspases
(physiology)
- Cell Line, Tumor
- Cysteine Proteinase Inhibitors
(pharmacology)
- Drug Synergism
- Humans
- Leupeptins
(pharmacology)
- Melanoma
(drug therapy, pathology)
- Mitochondria
(physiology)
- Myeloid Cell Leukemia Sequence 1 Protein
- Nitrophenols
(pharmacology)
- Piperazines
(pharmacology)
- Proteasome Inhibitors
- Proto-Oncogene Proteins c-bcl-2
(antagonists & inhibitors, metabolism, physiology)
- Sulfonamides
(pharmacology)
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