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Cancer Res. :中国研究者新发现一类化合物可抑制肿瘤干细胞生长

2012/01/17 来源:生物探索
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香港工业大学与北京大学深圳研究生院的研究人员新发现了一类化合物,可以抑制肿瘤干细胞的生长。

肿瘤干细胞不仅可以分裂生成肿瘤,而且还具有自我更新产生更多肿瘤干细胞的能力。尽管数量不多,但是由于能抵抗放疗及化疗,肿瘤干细胞极其难以杀死。

香港工业大学的Tao Ye与北京大学深圳研究生院的Hui Zhang及Junmin Quan联手发现了一类新的化合物,能够抑制肿瘤干细胞的生长。研究成果发表在2011年12月的Cancer Research上。

研究人员最初是为寻找一种针对LSD1小的抑制物,LSD1是一种在许多肿瘤中高表达的组蛋白脱甲基酶。他们发现了9种结构类似的化合物,能够在体外抑制LSD1的酶活性——其中最有效的抑制物是CBB1003和CBB1007。

研究人员在各种细胞系中对CBB1003和CBB1007进行试验,发现两种化合物均可抑制肿瘤干细胞的生长,而对癌症细胞或正常体细胞少有影响。该结果证实CBB1003与CB1007在肿瘤干细胞治疗中具有高度特异性。


Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties

Jing Wang, Fei Lu, Qi Ren, Hong Sun, Zhengshuang Xu, Rongfeng Lan, Yuqing Liu, David Ward, Junmin Quan, Tao Ye, and Hui Zhang

Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference–mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties.

文献链接:http://cancerres.aacrjournals.org/content/71/23/7238

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