Document Detail

Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells.
MedLine Citation:
PMID:  18667591     Owner:  NLM     Status:  MEDLINE    
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 micromol/L using two chemoresistant melanoma cell lines (M-14 and SK-Mel-19) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC(50) of 0.32 micromol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent.
Nicole Doudican; Adrianna Rodriguez; Iman Osman; Seth J Orlow
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-30
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  6     ISSN:  1541-7786     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-18     Completed Date:  2008-09-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1308-15     Citation Subset:  IM    
New York University School of Medicine, New York, NY 10016, USA.
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MeSH Terms
Apoptosis / drug effects*
Benzimidazoles / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Inhibitory Concentration 50
Mebendazole / pharmacology*
Melanocytes / drug effects,  metabolism
Melanoma / pathology*
Microtubules / drug effects,  pathology
Mitochondria / drug effects,  metabolism
Phosphorylation / drug effects
Protein Binding / drug effects
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Tubulin / chemistry
bcl-2-Associated X Protein / metabolism
Reg. No./Substance:
0/Benzimidazoles; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tubulin; 0/bcl-2-Associated X Protein; 31431-39-7/Mebendazole

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

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