Abstract:
: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.
journal_name
Chem Biol Drug Desjournal_title
Chemical biology & drug designauthors
Kaiser C,Meurice N,Gonzales IM,Arora S,Beaudry C,Bisanz KM,Robeson AC,Petit J,Azorsa DOdoi
10.1111/j.1747-0285.2010.00949.xsubject
Has Abstractpub_date
2010-04-01 00:00:00pages
360-8issue
4eissn
1747-0277issn
1747-0285pii
JPP949journal_volume
75pub_type
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