化療殺死腫瘤細胞，但它也造成身體其余部分十分嚴重的破壞,。由伊戈爾·南卡羅來納州大學(xué)藥學(xué)院Roninson領(lǐng)導(dǎo)的一個研究小組剛剛公布研究發(fā)現(xiàn)一類新的藥物可以減少化療給細胞帶來的不利影響,。傳統(tǒng)的抗癌藥物雖然是目前癌癥治療的主要手段，但具有副作用,，可損害健康的細胞,，并導(dǎo)致尚存的癌細胞生長，南卡羅來納州大學(xué)Roninson,。
傳統(tǒng)藥物導(dǎo)致癌癥死灰復(fù)燃,，部分是因為這些藥物既損害腫瘤細胞也損害患者的正常組織,，導(dǎo)致受藥物損傷的細胞發(fā)生許多變化包括衰老?？蓪?dǎo)致細胞衰老或老化,，也可以由傳統(tǒng)的抗癌藥物和其他因素造成DNA損傷誘導(dǎo)。
衰老細胞和其他受損的細胞已被證明是產(chǎn)生癌癥以及其他疾病如阿爾茨海默氏癥和關(guān)節(jié)炎等相關(guān)的一類細胞,。最近的研究已令人信服地證明這些衰老細胞分泌生物活性因子的重要性,，但沒有實際方法阻止這種模式的產(chǎn)生。在這項最新研究中,，一系列的化學(xué)物質(zhì)能抑制受損細胞的衰老和其分泌模式,。這種抑制是減少化療促進癌癥作用的關(guān)鍵。雅典（希臘）大學(xué)合著者Hippokratis Kiaris進行小鼠常用的抗癌藥物治療,，小鼠從這種治療恢復(fù)后,，藥物治療和未經(jīng)處理的小鼠都注射癌細胞。
引人注目的是,，抗癌藥物預(yù)處理的小鼠的腫瘤比未經(jīng)處理的小鼠更有效,。此外，抗癌藥物預(yù)處理的小鼠的血液中刺激腫瘤細胞生長的蛋白質(zhì)含量較高,。但老鼠給予一種名為Senexin A的藥物治療后,，腫瘤生長和腫瘤支持生長因子的生成都被抑制了。同時Senexin A也提高了常規(guī)藥物的抗腫瘤療效,。
Senexin A的作用蛋白是CDK8（細胞周期蛋白依賴激酶8）,。Senexin A是第一個CDK8的選擇性抑制劑，不同于其他已知CDK家族激酶,，CDK8雖然參與了基因表達調(diào)控,，但其不在細胞分裂中起作用。前期研究證實CDK8在結(jié)腸癌和黑色素瘤等癌癥類型中起到重要作用,。該研究團隊發(fā)現(xiàn)CDK8基因表達與乳腺癌和卵巢癌患者的未復(fù)發(fā)存活持續(xù)時間有著密切聯(lián)系,。這項最新研究結(jié)果證實了CDK8與損傷和衰老誘導(dǎo)的癌癥發(fā)生發(fā)展支持蛋白生成有關(guān)，CDK8的抑制類新藥有可能為不同類型癌癥帶來治療好處,。（生物谷：Bioon.com）
編譯自：A new approach to improving cancer chemotherapy
doi:10.1073/pnas.1206906109
PMC:
PMID:
Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities
Donald C. Portera,1, Elena Farmakib,1, Serena Altiliaa,c, Gary P. Schoolsc,d, et al.
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.
