8月6日，南卡罗来纳大学和南卡罗来纳医科大学的Igor Roninson领导国际研究小组在《美国国家科学院院刊》PNAS上发表题为“Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities”的论文，指出一类药物可用于治疗癌症和衰老相关的疾病。
Senex生物技术公司研发出可治疗肿瘤的新药
2000年，Roninson领导的研究小组在PNAS发表题为“Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases”的论文指出，一个被称为P21的蛋白质开启关于肿瘤和年龄相关疾病（如如阿尔茨海默氏病和关节炎）的多个基因。这些有害的变化尤其出现在衰老（老化）细胞中。随着时间的推移，细胞开始衰老，但是在多种因素（如癌症治疗中化疗药物和放射性辐射）损伤之后它有可能恢复正常。
新药CDK8抑制剂的分子机制
由于首次发现，Roninson尝试理解p21的惊人功效的作用机制，并开发出药物以阻止衰老细胞在不同疾病中的有害影响。在8月6日，Roninson和同事揭露这一具有远大的治疗前景的谜底。
在受损细胞中，P21基因的表达被开启。通过结合在细胞周期蛋白依赖性激酶（CDKs）上，P21蛋白阻止了细胞分裂。CDK是一个对于细胞分裂发挥关键作用的酶，p21结合后抑制其活性。这项新研究报告中， p21介导疾病的机理至少一部分体现在它对CDK8的作用上，后者调控多个基因的活性但不是细胞分裂必要的。P21能激活CDK8并开启CAK8调控的多个基因，这正好相反于它对其它CDK的作用。Roninson的研究小组和Senex生物技术公司一道研发能抑制CDK8的一种新药，他们发现这些药物克服一些癌症化疗过程中遇到的最棘手问题。
化疗可以缩小甚至消除肿瘤，但它也对身体其它部位造成十分严重的破坏——正常组织的损坏。化疗还可引起其它副作用，如：受损细胞合成的分子能促进生长，抗药性和化疗后剩余肿瘤细胞的扩散。
Senexin A新药的疗效
雅典大学（希腊）的Hippokratis Kiaris是共同作者之一，通过利用常要的化疗药物去处理健康小鼠，他发现化疗带来的副作用。小鼠恢复之后被注入肿瘤细胞，与没有经抗癌药处理的对照组相对，这些经过化疗方案处理过的小鼠更高效地形成肿瘤。
之前经抗癌药处理的老鼠血液含有较高的刺激肿瘤细胞生长的蛋白质，然而，当老鼠被注射Senexin A（Roninson研究小组开发一种人工合成的CDK8抑制剂）时，抗癌药不再刺激肿瘤的生长。
CDK8抑制剂提高了抗癌药物的功效，其被注射入肿瘤动物模型中能破坏肿瘤。CDK8抑制剂阻止了衰老细胞有害蛋白质的合成，这并不意味着扭转衰老，而是细胞中抑制肿瘤的必要程序。通过创造一种能抑制衰老有害影响的人工合成的化学物质，研究小组提供一个治疗癌症的医疗方法去治疗肿瘤和年龄有关的疾病，如阿尔茨海默氏症、动脉粥样硬化和关节炎。
Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities
Donald C. Portera, Elena Farmakib, Serena Altiliaa, Gary P. Schoolsc, Deborah K. Westa, Mengqian Chend, Bey-Dih Changa, Anatoliy T. Puzyreva, Chang-uk Limc,d, Rebecca Rokow-Kittella, Lawrence T. Friedhoffa, Athanasios G. Papavassilioub, Swathi Kalurupallec, Gregory Hurteauc, Jun Shie, Phil S. Barane, Balazs Gyorffyf, Mark P. Wentlandg, Eugenia V. Broudec, Hippokratis Kiarisb, Igor B. Roninsonc
Conventional chemotherapy not only kills tumor cells but also changes gene expression in treatment-damaged tissues, inducing production of multiple tumor-supporting secreted factors. This secretory phenotype was found here to be mediated in part by a damage-inducible cell-cycle inhibitor p21 (CDKN1A). We developed small-molecule compounds that inhibit damage-induced transcription downstream of p21. These compounds were identified as selective inhibitors of a transcription-regulating kinase CDK8 and its isoform CDK19. Remarkably, p21 was found to bind to CDK8 and stimulate its kinase activity. p21 and CDK8 also cooperate in the formation of internucleolar bodies, where both proteins accumulate. A CDK8 inhibitor suppresses damage-induced tumor-promoting paracrine activities of tumor cells and normal fibroblasts and reverses the increase in tumor engraftment and serum mitogenic activity in mice pretreated with a chemotherapeutic drug. The inhibitor also increases the efficacy of chemotherapy against xenografts formed by tumor cell/fibroblast mixtures. Microarray data analysis revealed striking correlations between CDK8 expression and poor survival in breast and ovarian cancers. CDK8 inhibition offers a promising approach to increasing the efficacy of cancer chemotherapy.
文献链接：Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities
Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases
Bey-Dih Chang, Keiko Watanabe, Eugenia V. Broude, Jing Fang, Jason C. Poole, Tatiana V. Kalinichenko, Igor B. Roninson
Induction of cyclin-dependent kinase inhibitor p21Waf1/Cip1/Sdi1 triggers cell growth arrest associated with senescence and damage response. Overexpression of p21 from an inducible promoter in a human cell line induces growth arrest and phenotypic features of senescence. cDNA array hybridization showed that p21 expression selectively inhibits a set of genes involved in mitosis, DNA replication, segregation, and repair. The kinetics of inhibition of these genes on p21 induction parallels the onset of growth arrest, and their reexpression on release from p21 precedes the reentry of cells into cell cycle, indicating that inhibition of cell-cycle progression genes is a mechanism of p21-induced growth arrest. p21 also up-regulates multiple genes that have been associated with senescence or implicated in age-related diseases, including atherosclerosis, Alzheimer's disease, amyloidosis, and arthritis. Most of the tested p21-induced genes were not activated in cells that had been growth arrested by serum starvation, but some genes were induced in both forms of growth arrest. Several p21-induced genes encode secreted proteins with paracrine effects on cell growth and apoptosis. In agreement with the overexpression of such proteins, conditioned media from p21-induced cells were found to have antiapoptotic and mitogenic activity. These results suggest that the effects of p21 induction on gene expression in senescent cells may contribute to the pathogenesis of cancer and age-related diseases.
