雷公藤內(nèi)酯醇是中藥雷公藤的主要生物活性成分,，具有包括抗腫瘤在內(nèi)的多重生物學(xué)作用。中科院上海藥物研究所繆澤鴻課題組,、李援朝課題組,、丁健課題組與意大利博洛尼亞大學(xué)Giovanni Capranico實(shí)驗(yàn)室合作，在雷公藤內(nèi)酯醇及其衍生物的抗腫瘤作用和機(jī)制研究中取得階段性進(jìn)展,。
在闡明C14β位羥基取代的雷公藤內(nèi)酯醇衍生物具有選擇性體內(nèi)抗腫瘤作用 (J Med Chem. 2009; 52: 5115–5123) 的基礎(chǔ)上,，研究發(fā)現(xiàn)雷公藤內(nèi)酯醇可升高細(xì)胞內(nèi)低氧誘導(dǎo)因子1α(HIF-1α)水平卻降低其轉(zhuǎn)錄活性，與其抗腫瘤作用相關(guān) (Mol Cancer. 2010; 9:268),。已有研究顯示,，雷公藤內(nèi)酯醇可以與通用轉(zhuǎn)錄因子TFIIH大亞基XPB直接結(jié)合，并引起RNA聚合酶II(RNAPII)大亞基Rpb1降解,。
該合作研究深入揭示了雷公藤內(nèi)酯醇作用于這一核心靶點(diǎn)的分子基礎(chǔ)和意義,。雷公藤內(nèi)酯醇降低Rpb1水平與其細(xì)胞毒活性緊密相關(guān)，即阻滯RNAPII于基因的啟動(dòng)子處,，減少基因啟動(dòng)子和外顯子處染色質(zhì)結(jié)合的RNAPII,，增加Rpb1羧基末端結(jié)構(gòu)域的磷酸化 (5位絲氨酸) 和泛素化。蛋白酶體抑制劑或CDK7抑制劑可減低雷公藤內(nèi)酯醇降解Rpb1的能力,。研究人員由此發(fā)現(xiàn)雷公藤內(nèi)酯醇觸發(fā)CDK7介導(dǎo)RNAPII降解的新模式,，提出了雷公藤內(nèi)酯醇結(jié)合XPB,、降解RNAPII的通用機(jī)制。該機(jī)制可以很好地解釋雷公藤內(nèi)酯醇包括其強(qiáng)效抗腫瘤在內(nèi)的多重治療學(xué)特性 (Cancer Res.2012; doi:10.1158/0008-5472.CAN-12-1006),。
研究人員還受邀撰寫雷公藤內(nèi)酯醇專題綜述,，系統(tǒng)總結(jié)了雷公藤內(nèi)酯醇的結(jié)構(gòu)修飾、構(gòu)效關(guān)系,、作用與機(jī)制以及臨床開發(fā)的研究進(jìn)展 (Nat Prod Rep. 2012; 29: 457-475),。（生物谷Bioon.com）
doi: 10.1158/0008-5472.CAN-12-1006
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Natural product triptolide mediates cancer cell death by triggering CDK7-dependent degradation of RNA polymerase II
Stefano Giustino Manzo, Zhao-Li Zhou, Ying-Qing Wang, Jessica Marinello, Jin-Xue He, Yuan-Chao Li, Jian Ding, Giovanni Capranico, and Ze-Hong Miao
Triptolide is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biological properties, including anticancer properties. Among its many putative targets, this compound has been reported to bind to XPB, the largest subunit of general transcription factor TFIIH, and to cause degradation of the largest subunit Rpb1 of RNA polymerase II (RNAPII). In this study, we clarify multiple important questions concerning the significance and basis for triptolide action at this core target. Triptolide decreased Rpb1 levels in cancer cells in a manner that was correlated tightly with its cytotoxic activity. Compound exposure blocked RNAPII at promoters and decreased chromatin-bound RNAPII, both upstream and within all genes that were examined, also leading to Ser5 hyperphosphorylation and increased ubiqutination within the Rbp1 carboxy-terminal domain. Notably, co-treatment with inhibitors of the proteasome or the cyclin-dependent kinase CDK7 inhibitors abolished the ability of triptolide to ablate Rpb1. Together, our results show that triptolide triggers a CDK7-mediated degradation of RNAP II that may offer an explanation to many of its therapeutic properties, including its robust and promising anticancer properties.
