Arresting cancer proliferation by small-molecule gene regulation
Arresting cancer proliferation by small-molecule gene regulation
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DOI：
10.1016/j.chembiol.2004.09.004
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发表时间：
2004-11-01
影响因子：
--
通讯作者：
Gottesfeld, JM
中科院分区：
文献类型：
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作者：
Dickinson, LA;Burnett, R;Gottesfeld, JM
筛选了吡咯-咪唑聚酰胺-DNA烷化剂（苯丁酸氮芥）缀合物的小文库对人结肠癌细胞系的形态和生长特征的影响，并鉴定了导致细胞停滞在细胞周期的G2/M期的化合物。微阵列分析表明，组蛋白Hoc基因是显着下调这种聚酰胺。RT-PCR和Western印迹实验证实了这一结果，并且针对Hoc mRNA的siRNA产生相同的细胞应答。令人惊讶的是，H4蛋白减少>50%不会导致整体基因表达的广泛变化。通过LM-PCR证实了细胞培养物中Hoc基因编码区内的序列特异性烷基化。该化合物在广泛的癌细胞系中具有活性，并且经处理的细胞在裸鼠中不会形成肿瘤。该化合物在体内也有活性，可阻断小鼠肿瘤生长，无明显动物毒性。
A small library of pyrrole-imidazole polyamide-DNA alkylator (chlorambucil) conjugates was screened for effects on morphology and growth characteristics of a human colon carcinoma cell line, and a compound was identified that causes cells to arrest in the G2/M stage of the cell cycle. Microarray analysis indicates that the histone Hoc gene is significantly downregulated by this polyamide. RT-PCR and Western blotting experiments confirm this result, and siRNA to Hoc mRNA yields the same cellular response. Strikingly, reduction of H4 protein by >50% does not lead to widespread changes in global gene expression. Sequence-specific alkylation within the coding region of the Hoc gene in cell culture was confirmed by LM-PCR. The compound is active in a wide range of cancer cell lines, and treated cells do not form tumors in nude mice. The compound is also active in vivo, blocking tumor growth in mice, without obvious animal toxicity.