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BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis.

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.
AuthorsLeslie A Miller, Nathaniel B Goldstein, Widya U Johannes, Christine H Walton, Mayumi Fujita, David A Norris, Yiqun G Shellman
JournalThe Journal of investigative dermatology (J Invest Dermatol) Vol. 129 Issue 4 Pg. 964-71 (Apr 2009) ISSN: 1523-1747 [Electronic] United States
PMID18987671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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
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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