發(fā)表在3月21日《化學(xué)與生物學(xué)》（Chemistry & Biology）封面上的最新一項(xiàng)研究,，發(fā)現(xiàn)了兩種新的抗癌化合物,，它們能夠致使含有RAS癌基因的癌細(xì)胞非程序性凋亡。
RAS是最常見的癌基因,，它所編碼的RAS蛋白是一種小G蛋白,，其活性依賴與GTP的結(jié)合，突變的RAS蛋白質(zhì)喪失了水解GTP的活性,，從而激活RAS通路下游相關(guān)基因,，導(dǎo)致細(xì)胞癌變。來自美國哥倫比亞大學(xué)的研究人員以RAS突變致癌的癌細(xì)胞為材料,，通過聯(lián)合致死篩選（synthetic lethal screening）的方法,，從47725個人工合成或天然產(chǎn)物的衍生物中篩選出能致死該癌細(xì)胞的兩種小分子化合物RSL3和RSL5。
聯(lián)合致死的原理是：如果突變B特異性使具有突變A的細(xì)胞死亡,，那么突變B即對突變A具有聯(lián)合致死效應(yīng),。基于該技術(shù)篩選出的RSL3和RSL5能夠使含有RAS癌基因的細(xì)胞死亡,，對其它細(xì)胞的無毒性或毒性很小,，其中RSL3特異的使RAS癌基因的細(xì)胞死亡，而對其它細(xì)胞沒有影響,。
進(jìn)一步研究發(fā)現(xiàn),，RSL3和RSL5的致死效應(yīng)依賴于鐵離子和RAS-RAF-MEK氧化作用。RNA干擾實(shí)驗(yàn)表明,，線粒體內(nèi)的壓力依賴的陰離子通道（VDACs）參與了RSL5的致死過程,，但與RSL3的致死作用無關(guān)。鐵離子鰲合劑能同時抑制RSL5和RSL3誘導(dǎo)的癌細(xì)胞凋亡,，表明鐵離子在誘導(dǎo)細(xì)胞死亡過程中發(fā)揮了重要作用,，而具有RAS癌基因的細(xì)胞能夠通過上調(diào)鐵傳遞蛋白受體1和下調(diào)鐵蛋白的作用增家細(xì)胞內(nèi)的鐵含量。
傳統(tǒng)的抗癌藥物開發(fā)僅以單個癌基因相關(guān)蛋白為靶標(biāo),，而本研究所采用的聯(lián)合致死篩選方法則可以針對癌基因的作用方式進(jìn)行藥物篩選,，具有更廣泛的靶標(biāo),，展現(xiàn)了比較好的藥物開發(fā)前景，同時該方法也有利于進(jìn)一步了解癌基因的作用機(jī)制,。（科學(xué)網(wǎng) 穆宏平/編譯）
生物谷推薦原始出處：
（Chemistry & Biology）,，Vol 15, 234-245, 21 March 2008，Wan Seok Yang and Brent R. Stockwell
Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells
Wan Seok Yang1 and Brent R. Stockwell1,2,
1 Department of Biological Sciences, Columbia University, Fairchild Center, MC2406, 1212 Amsterdam Avenue, New York, NY 10027, USA
2 Department of Chemistry, Columbia University, Fairchild Center, MC2406, 1212 Amsterdam Avenue, New York, NY 10027, USA
Corresponding author
Brent R. Stockwell
[email protected]
Summary
We screened small molecules to identify two compounds, which we named RSL3 and RSL5, that have increased lethality in the presence of oncogenic RAS. Counter screening with biologically active compounds defined aspects of the mechanism of action for RSL3 and RSL5, such as a nonapoptotic, MEK-dependent, and iron-dependent oxidative cell death. Erastin, a previously reported compound with RAS-selective lethality, showed similar properties. RNA interference experiments targeting voltage-dependent anion channel 3 (VDAC3), a target of erastin, demonstrated that RSL5 is a scaffold that acts through VDACs to activate the observed pathway. RSL3 activated a similar death mechanism but in a VDAC-independent manner. We found that cells transformed with oncogenic RAS have increased iron content relative to their normal cell counterparts through upregulation of transferrin receptor 1 and downregulation of ferritin heavy chain 1 and ferritin light chain.
