Document Detail


Chemogenomic analysis identifies Macbecin II as a compound specific for SMAD4-negative colon cancer cells.
MedLine Citation:
PMID:  20331650     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The tumor suppressor gene, SMAD4, is mutated in approximately 30% of colon cancers. To identify compounds with enhanced potency on cells with a SMAD4-negative context, we combined genomic and cheminformatic analyses of publicly available data relating to the colon cancer cell lines within the NCI60 panel. Two groups of cell lines were identified with either wild-type or negative SMAD4 status. A cheminformatic analysis of the NCI60 screening data was carried out, which led to the identification of 14 compounds that preferentially inhibited cell growth of the SMAD4-negative cell lines. Using cell viability assays, the effect of these compounds was validated on four colon cancer cell lines: HCT-116 and HCT-15 (SMAD4-expressing), and HT-29 and COLO-205 (SMAD4-negative). Our data identified Macbecin II, a hydroquinone ansamycin antibiotic, as having increased potency in the SMAD4-negative cells compared to SMAD4 wild-type cells. In addition, we showed that silencing of SMAD4 using siRNA in HCT-116 enhanced Macbecin II potency. Our results demonstrate that Macbecin II is specifically active in colon cancer cells having a SMAD4-negative background and thus is a potential candidate for further investigation in a drug discovery perspective.
Authors:
Christine Kaiser; Nathalie Meurice; Irma M Gonzales; Shilpi Arora; Christian Beaudry; Kristen M Bisanz; Alexander C Robeson; Joachim Petit; David O Azorsa
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemical biology & drug design     Volume:  75     ISSN:  1747-0285     ISO Abbreviation:  Chem Biol Drug Des     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-03-24     Completed Date:  2010-06-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101262549     Medline TA:  Chem Biol Drug Des     Country:  England    
Other Details:
Languages:  eng     Pagination:  360-8     Citation Subset:  IM    
Affiliation:
Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / chemistry,  pharmacology*,  therapeutic use
Apoptosis
Benzoquinones / chemistry,  pharmacology*,  therapeutic use
Cell Line, Tumor
Colonic Neoplasms / drug therapy*,  metabolism
Drug Discovery
Gene Silencing
Genomics
HCT116 Cells
HT29 Cells
Humans
Lactams, Macrocyclic / chemistry,  pharmacology*,  therapeutic use
RNA Interference
RNA, Small Interfering
Smad4 Protein / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Benzoquinones; 0/Lactams, Macrocyclic; 0/RNA, Small Interfering; 0/Smad4 Protein; 73341-73-8/macbecin II

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


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