一種用于治療精神分裂癥的抗精神病的藥物通過(guò)幫助癌癥干細(xì)胞分化成威脅性較低的細(xì)胞類型,，似乎也作用于癌癥干細(xì)胞,。5月24日的Cell雜志上刊登的一則研究報(bào)道：為了尋找能選擇性地抑制人類癌癥干細(xì)胞，研究人員篩選了數(shù)百種化合物,，這一研究成果可能會(huì)很快走上臨床試驗(yàn)。
麥克馬斯特大學(xué)Mickie Bhatia,，論文的主要作者說(shuō)：你必須找到那些能真正選擇性作用于癌癥干細(xì)胞的藥物,，我們研究工作進(jìn)行一段時(shí)間后，發(fā)現(xiàn)很難找到確切的物質(zhì),。
近30年以來(lái),，癌癥患者的生存很大程度上是不變的。通過(guò)解決數(shù)量上少以及化療耐藥的腫瘤干細(xì)胞,，很多人相信癌癥治療會(huì)取得更大成就,。
與正常的干細(xì)胞不一樣，癌癥干細(xì)胞分化成穩(wěn)定地,、未分化的細(xì)胞類型的趨勢(shì)不明顯,。Bhatia的研究小組利用癌癥干細(xì)胞的這種差異性，進(jìn)行了活性化合物的篩選工作,。
通過(guò)測(cè)試數(shù)百種化合物,，他們確定了近20個(gè)潛在的癌癥干細(xì)胞特異性藥物。其中一個(gè)似乎最有前途的就是抗精神病藥物——硫利達(dá)嗪,。硫利達(dá)嗪是眾所周知的針對(duì)大腦中的多巴胺受體,，治療精神分裂癥的藥物。這種藥物不會(huì)殺死癌癥干細(xì)胞,，但卻能促進(jìn)干細(xì)胞分化,，從而耗盡細(xì)胞的自我更新。
研究人員發(fā)現(xiàn),，硫利達(dá)嗪在殺死白血病干細(xì)胞的同時(shí),，而不影響正常的血液干細(xì)胞。通過(guò)比較白血病與正常血細(xì)胞的蛋白質(zhì),，研究人員解釋這一藥物的特異性,。白血病細(xì)胞在其表面表達(dá)多巴胺受體，但正常的造血干細(xì)胞不表達(dá),。研究人員還發(fā)現(xiàn)多巴胺受體也在一些乳腺癌干細(xì)胞上表達(dá),。
Bhatia說(shuō)，這提示我們多巴胺受體可能作為腫瘤干細(xì)胞的生物標(biāo)志物。
鑒于研究結(jié)果,，Bhatia的團(tuán)隊(duì)正申請(qǐng)一項(xiàng)旨在FDA批準(zhǔn)的硫利達(dá)嗪與標(biāo)準(zhǔn)抗癌藥物相結(jié)合的治療成人急性髓細(xì)胞性白血病的臨床試驗(yàn),。（生物谷：Bioon.com）
doi:10.1016/j.cell.2012.03.049
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Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells
Eleftherios Sachlos, Ruth M. Risue?o, Sarah Laronde, Zoya Shapovalova, Jong-Hee Lee, Jennifer Russell, Monika Malig, Jamie D. McNicol, Aline Fiebig-Comyn, Monica Graham, Marilyne Levadoux-Martin, Jung Bok Lee, Andrew O. Giacomelli, John A. Hassell, Daniela Fischer-Russell, Michael R. Trus, Ronan Foley, Brian Leber, Anargyros Xenocostas, Eric D. Brown, Tony J. Collins, Mickie Bhatia.
Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.
