Document Detail


Synthesis and identification of small molecules that potently induce apoptosis in melanoma cells through G1 cell cycle arrest.
MedLine Citation:
PMID:  15954774     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Late-stage malignant melanoma is a cancer that is refractory to current chemotherapeutic treatments. The average survival time for patients with such a diagnosis is 6 months. In general, the vast majority of anticancer drugs operate through induction of cell cycle arrest and cell death in either the DNA synthesis (S) or mitosis (M) phase of the cell cycle. Unfortunately, the same mechanisms that melanocytes possess to protect cells from DNA damage often confer resistance to drugs that derive their toxicity from S or M phase arrest. Described herein is the synthesis of a combinatorial library of potential proapoptotic agents and the subsequent identification of a class of small molecules (triphenylmethylamides, TPMAs) that arrest the growth of melanoma cells in the G1 phase of the cell cycle. Several of these TPMAs are quite potent inducers of apoptotic death in melanoma cell lines (IC(50) approximately 0.5 muM), and importantly, some TPMAs are comparatively nontoxic to normal cells isolated from the bone marrow of healthy donors. Furthermore, the TPMAs were found to dramatically reduce the level of active nuclear factor kappa-B (NFkappaB) in the cell; NFkappaB is known to be constitutively active in melanoma, and this activity is critical for the proliferation of melanoma cells and their evasion of apoptosis. Compounds that reduce the level of NFkappaB and arrest cells in the G1 phase of the cell cycle can provide insights into the biology of melanoma and may be effective antimelanoma agents.
Authors:
Robin S Dothager; Karson S Putt; Brittany J Allen; Benjamin J Leslie; Vitaliy Nesterenko; Paul J Hergenrother
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  127     ISSN:  0002-7863     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-06-15     Completed Date:  2005-08-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8686-96     Citation Subset:  IM    
Affiliation:
Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, USA.
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MeSH Terms
Descriptor/Qualifier:
Amides / chemical synthesis*,  chemistry,  pharmacology*,  toxicity
Antineoplastic Agents / chemical synthesis,  pharmacology,  toxicity
Apoptosis / drug effects*
Bone Marrow Cells / drug effects
Cell Line, Tumor
G1 Phase / drug effects*
Humans
Melanoma / drug therapy*,  pathology
NF-kappa B / antagonists & inhibitors
Terphenyl Compounds / chemical synthesis*,  pharmacology*,  toxicity
Chemical
Reg. No./Substance:
0/Amides; 0/Antineoplastic Agents; 0/NF-kappa B; 0/Terphenyl Compounds

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


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