美國加州大學(xué)戴維斯分校一個研究小組最近發(fā)現(xiàn)了一種可以阻斷腎癌細(xì)胞自我修復(fù)的新方法,，這一成果有望使腎癌化療更為有效，也更易承受,。
癌細(xì)胞最典型的特點就是能夠快速復(fù)制,，而腎癌是最難治療的癌癥之一，因為它在擴(kuò)散到其他器官之前通常并無明顯癥狀,。目前的一些腎癌化療方案可以減緩癌細(xì)胞復(fù)制,，延長患者存活期，但藥物毒性也會導(dǎo)致嚴(yán)重副作用。有關(guān)專家指出,，如果能進(jìn)一步提高腎癌化療的有效性,，就可以最大限度殺死癌細(xì)胞，減少化療次數(shù)和用藥量,，從而減少患者痛苦,。
研究小組在新一期《癌癥生物學(xué)和療法》雜志上介紹說，在包括腎癌在內(nèi)的多種癌癥中,，p21基因都扮演了重要角色,，它幫助修復(fù)癌細(xì)胞的脫氧核糖核酸（DNA），尤其在面對腎癌化療藥物攻擊時,，它可以幫助癌細(xì)胞自我修復(fù),，從而降低化療有效性?？蒲腥藛T試圖找到能夠阻斷p21基因通路的“特效”化合物,。
據(jù)研究負(fù)責(zé)人羅伯特·魏斯介紹，他們經(jīng)過多次實驗,，終于發(fā)現(xiàn)3種很特別的化合物能夠顯著降低p21基因的表達(dá),，阻斷腎癌細(xì)胞自我修復(fù)的過程，使化療藥物更加容易對癌細(xì)胞產(chǎn)生作用,。
研究小組還將深入研究這3種化合物,，以確定它們能發(fā)揮效用的最低濃度，并進(jìn)一步優(yōu)化它們的抗癌特性,。之后,，他們將把3種化合物與標(biāo)準(zhǔn)的腎癌化療方案相結(jié)合，以探索出新的療法,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cancer Biology & Therapy,，volume 7, issue 12, 2015 - 2022，See-Hyoung Park,，Ruiwu Liu
High throughput screening of a small molecule one-bead-one-compound combinatorial library to identify attenuators of p21 as chemotherapy sensitizers
See-Hyoung Park, Xiaobing Wang, Ruiwu Liu, Kit S. Lam and Robert H Weiss
Kidney cancer is notoriously difficult to treat when metastatic due to its resistance to conventional chemotherapy. p21 is a cyclin kinase inhibitor which, in many tumor cell lines, conveys an anti-apoptotic function through its induction by the DNA damage responsive p53 pathway, such that attenuation of p21 sensitizes several disparate cancer cell lines to DNA-damaging chemotherapy. Since clinical applications with therapeutic antisense and siRNA approaches are problematic, we sought to discover other methods to inhibit p21 which are more readily translatable to the clinic. Utilizing an on-bead enzyme-linked colorimetric binding assay, we screened a diverse one-bead-one-compound combinatorial small molecule library, and identified 12 candidate compounds which bind p21. Each of the 12 candidate compounds was synthesized and tested individually, and 3 ligands were found which had the highest p21 binding affinity and yielded similar chemical structure. These 3 compounds caused dose-dependent cytotoxicity as well as apoptosis when exposed to two RCC cell lines. In addition, these compounds sensitized cells to apoptosis when incubated with doxorubicin such that a lower dose of doxorubicin was required in the presence of the compounds for equivalent cell killing. Interestingly, a representative of the 3 compounds decreased p21 levels by specific induction of ubiquitin-dependent proteosome degradation. Thus, by high throughput screening of thousands of candidate small molecules, we have identified compounds which attenuate p21, cause RCC cell apoptosis, and sensitize RCC cells to DNA-damaging chemotherapy. These compounds are currently being evaluated in in vivo assays as potential novel therapeutic for RCC.
