Document Detail

BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis.
MedLine Citation:
PMID:  18987671     Owner:  NLM     Status:  MEDLINE    
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.
Leslie A Miller; Nathaniel B Goldstein; Widya U Johannes; Christine H Walton; Mayumi Fujita; David A Norris; Yiqun G Shellman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2008-11-06
Journal Detail:
Title:  The Journal of investigative dermatology     Volume:  129     ISSN:  1523-1747     ISO Abbreviation:  J. Invest. Dermatol.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-03-26     Completed Date:  2009-04-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0426720     Medline TA:  J Invest Dermatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  964-71     Citation Subset:  IM    
Department of Dermatology, School of Medicine, University of Colorado Denver, Aurora, Colorado 80010, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Biphenyl Compounds / pharmacology*
Caspases / physiology
Cell Line, Tumor
Cysteine Proteinase Inhibitors / pharmacology*
Drug Synergism
Leupeptins / pharmacology*
Melanoma / drug therapy*,  pathology
Mitochondria / physiology
Nitrophenols / pharmacology*
Piperazines / pharmacology
Proteasome Endopeptidase Complex / antagonists & inhibitors*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*,  metabolism,  physiology
Sulfonamides / pharmacology*
Grant Support
P30 CA 046934/CA/NCI NIH HHS; R01AR26427-18/AR/NIAMS NIH HHS
Reg. No./Substance:
0/ABT-737; 0/Antineoplastic Agents; 0/Biphenyl Compounds; 0/Cysteine Proteinase Inhibitors; 0/Leupeptins; 0/Nitrophenols; 0/PMAIP1 protein, human; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Sulfonamides; 0/myeloid cell leukemia sequence 1 protein; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; EC 3.4.22.-/Caspases; EC Endopeptidase Complex

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for...
Next Document:  Reduced oxazolone-induced skin inflammation in MAPKAP kinase 2 knockout mice.