中國(guó)香港理工大學(xué),、北京大學(xué)深圳研究生院和美國(guó)內(nèi)華達(dá)癌癥研究所聯(lián)合執(zhí)行一項(xiàng)合作性抗癌研究，開(kāi)發(fā)出一類新的特異地靶向多能性癌細(xì)胞的LSD1抑制物,，其中LSD1是一種在很多腫瘤中高度表達(dá)的組蛋白去甲基酶,。這類抑制物是由9種結(jié)構(gòu)類似的化學(xué)物組成,，它們?cè)隗w外能夠抑制LSD1的酶活性---當(dāng)中最有效的是CBB1003和CBB1007。
這種前沿性研究結(jié)合了三個(gè)研究小組的努力,，其中就包括香港理工大學(xué)應(yīng)用生物學(xué)和化學(xué)技術(shù)部門(mén)副教授Tao Ye領(lǐng)導(dǎo)的一個(gè)研究小組,。這次突破可能有助于選擇性移除癌干細(xì)胞 (cancer stem cell，譯者注：也常譯作腫瘤干細(xì)胞或癌癥干細(xì)胞),，潛在性地提供一種根除癌癥的新策略,。
癌癥是中國(guó)和全世界人們死亡的一種主要原因，但是人們很難去除存在的癌癥起始細(xì)胞/癌干細(xì)胞(cancer initiating cells/cancer stem cells),。盡管癌干細(xì)胞存在的數(shù)量非常少,，但是它們能夠增殖和自我更新，因而是多能性的和多向分化的,，也就是它們有能力分化為組成全部腫瘤塊的各種更加異質(zhì)的癌細(xì)胞,。作為干細(xì)胞，它們更加能夠抵抗大多數(shù)常規(guī)的抗癌治療如化療或放療,，因?yàn)樗鼈冊(cè)诩?xì)胞周期調(diào)控和DNA修復(fù)過(guò)程中存在差別,。在常規(guī)癌癥治療后，它們也作為腫瘤轉(zhuǎn)移和抗藥物治療的復(fù)發(fā)性癌癥的來(lái)源,。當(dāng)前,，還沒(méi)有化學(xué)抑制物或其他試劑能夠特異性地和選擇性地靶向癌干細(xì)胞。開(kāi)發(fā)靶向癌干細(xì)胞的化合物是治療惡性癌癥的迫切需求,。
根據(jù)Ye博士的觀點(diǎn),，新的LSD1抑制物具有潛在的臨床應(yīng)用：它們能夠被用治療惡性生殖細(xì)胞瘤如畸胎瘤,、胚胎瘤(embryonic carcinoma),、精原細(xì)胞瘤、絨毛膜瘤和卵黃囊瘤,。這些腫瘤通過(guò)手術(shù)或順鉑(cis-platinum)進(jìn)行治療,，但是在初始治療后，這些腫瘤總是變得能夠抵抗順鉑藥物,。迄今為止,，LSD1抑制物對(duì)這些具有干細(xì)胞性質(zhì)的多能性癌細(xì)胞是高度有效的。LSD1抑制物可能也能夠被用來(lái)移除干細(xì)胞治療期間產(chǎn)生的畸胎瘤/胚胎瘤,。干細(xì)胞或誘導(dǎo)性多功能干細(xì)胞(iPSC)治療的一個(gè)主要問(wèn)題就是胚胎干細(xì)胞或誘導(dǎo)性多功能干細(xì)胞在受者器官中不完全分化產(chǎn)生胚胎瘤/畸胎瘤,。因?yàn)長(zhǎng)SD1抑制物選擇性地抑制這些多能性胚胎瘤和畸胎瘤，所以LSD1抑制物可能有助于確保干細(xì)胞治療的成功應(yīng)用,。更重要的是,，因?yàn)榛チ?胚胎瘤是多能性癌干細(xì)胞，研究人員將會(huì)去研究其他器官特異性的癌癥如乳腺癌,、卵巢癌,、肺癌和腦癌的癌干細(xì)胞是否也對(duì)LSD1抑制物敏感,。進(jìn)一步研究表明LSD1抑制物也能夠被用來(lái)抑制很多癌干細(xì)胞樣細(xì)胞諸如乳腺癌和卵巢癌。
作為一名化學(xué)生物學(xué)領(lǐng)域的科學(xué)帶頭人,，Tao Ye博士已獲得香港研究資助局(Research Grants Council)的大量資金資助,。從2010年開(kāi)始，他已在影響因子大于5的頂尖研究期刊上發(fā)表12篇原創(chuàng)性研究論文,。
Tao Ye博士的抗癌藥物項(xiàng)目也得到方樹(shù)福堂基金會(huì)(Fong Shu Fook Tong Foundation)和郭謝碧蓉基金會(huì)(Joyce M. Kuok Foundation)的慷慨資助,。(生物谷：towersimper編譯)
doi:10.1158/0008-5472.CAN-11-0896
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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.
