用一種小分子“喚醒”能導(dǎo)致細(xì)胞死亡的關(guān)鍵酶caspase-3,，科學(xué)家們發(fā)現(xiàn)了一種可讓某些癌細(xì)胞自我毀滅的方法。他們?cè)?0月出版的《自然—化學(xué)生物學(xué)》期刊上報(bào)告了這種新方法,。
通常情況下,，caspase-3以原酶的形式存在，也就是說(shuō)需要有進(jìn)一步的程序才能使之成為活性酶,。這個(gè)過(guò)程一般是由其他蛋白酶caspase來(lái)執(zhí)行,，當(dāng)細(xì)胞出現(xiàn)問(wèn)題時(shí)，caspase以信號(hào)的形式提供服務(wù),。這種信號(hào)的出現(xiàn)表明需要細(xì)胞死亡或凋亡?，F(xiàn)在，Paul Hergenrother和同事利用合成化合物PAC-1來(lái)誘導(dǎo)procaspase-3進(jìn)入程序化過(guò)程,，產(chǎn)生caspase-3讓細(xì)胞死亡,。他們的研究表明，在多種類型的癌細(xì)胞中,，細(xì)胞的死亡與細(xì)胞中 procaspase-3的水平有關(guān),。低劑量PAC-1就會(huì)產(chǎn)生更多的導(dǎo)致細(xì)胞死亡的procaspase-3，同時(shí)卻不損害健康細(xì)胞,。
實(shí)驗(yàn)表明,，procaspase-3在不同個(gè)體細(xì)胞中的含量是不一樣的，這也許會(huì)解釋為什么部分患者比其他患者對(duì)這種治療反應(yīng)更強(qiáng)烈,。為癌癥患者提供因人而異的治療方法是一種夢(mèng)想,，新研究為之展示了一種新的可能性。
英文原文：
Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy
Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, concentrations of procaspase-3 in certain cancerous cells are significantly higher than those in noncancerous controls. Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. We found that PAC-1 retarded the growth of tumors in three different mouse models of cancer, including two models in which PAC-1 was administered orally. PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3, a transformation that allows induction of apoptosis even in cells that have defective apoptotic machinery. The direct activation of executioner caspases is an anticancer strategy that may prove beneficial in treating the many cancers in which procaspase-3 concentrations are elevated.
