Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
Chem Biol Drug Des. 2010 Apr;75(4):360-8. doi: 10.1111/j.1747-0285.2010.00949.x.
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.
抑癌基因 SMAD4 在大约 30%的结肠癌中发生突变。为了鉴定对 SMAD4 阴性背景的细胞具有增强效力的化合物，我们结合了对 NCI60 面板中结肠癌细胞系的公开可用数据进行的基因组和化学信息学分析。鉴定出两组具有野生型或阴性 SMAD4 状态的细胞系。对 NCI60 筛选数据进行了化学信息学分析，从而鉴定出 14 种优先抑制 SMAD4 阴性细胞系细胞生长的化合物。使用细胞活力测定法，在四种结肠癌细胞系（HCT-116 和 HCT-15（表达 SMAD4）以及 HT-29 和 COLO-205（SMAD4 阴性））上验证了这些化合物的作用。我们的数据确定 Macbecin II 是一种对具有阴性 SMAD4 的细胞比野生型 SMAD4 细胞具有更高效力的对苯二酚 ansamycin 抗生素。此外，我们表明，使用 siRNA 沉默 HCT-116 中的 SMAD4 增强了 Macbecin II 的效力。我们的结果表明，Macbecin II 特异性地在具有阴性 SMAD4 背景的结肠癌细胞中具有活性，因此是在药物发现方面进一步研究的潜在候选物。
