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GT198蛋白是抗癌化药和抗癌草药的靶点

GT198 Is a Target of Oncology Drugs and Anticancer Herbs

摘要: 肿瘤血管生成是癌症的一个特征。一些抗血管生成的抗癌药物已被证明临床有疗效。我们之前的研究显示,在包括口腔癌在内的人类实体瘤中,GT198 蛋白(基因符号PSMC3IP,又称为Hop2)是一个诱导血管生成的癌蛋白。本研究结果表明,十几种临床抗癌化疗药物,和几种临床成功的抗癌草药,都能直接抑制GT198蛋白靶点。GT198是一个能与DNA结合的DNA修复蛋白。利用体外DNA结合法检测GT198活性,我们测试了129个美国NCI收集的临床抗癌化疗药物。发现体外直接抑制GT198的化药包括但不限于米托蒽醌、多柔比星(阿霉素)、紫杉醇、依托泊苷、放线菌素D和伊马替尼(格列卫)。紫杉醇和依托泊苷具有较高的结合亲和力,而多柔比星由于竞争性抑制GT198,具有较高的结合效力。由于GT198与DNA拓扑异构酶有蛋白序列同源性,而DNA拓扑异构酶是过去认为的药物靶点,因此,GT198蛋白很可能是个以前未被认知的药物新靶点。为了寻求更高效的GT198抑制剂,我们进一步测试了几种抗癌草药的提取物。发现具有高亲和力和高效力的阳性抑制草药都是临床上已经有成功历史的抗癌草药,包括牙买加的多香果(Allspice)、中国的皂角刺(Gleditsia sinensis L.),和厄瓜多尔的BIRM。我们使用有机化学方法对多香果进行了部分纯化,证明用GT198为靶标,以体外DNA结合法追踪测活,可以高效快速纯化天然产物。综上表明,此项研究揭示了GT198是多种抗癌化药的新靶点。这项研究还提供了一个鉴定化合物与纯化天然产物的优异药物靶标。特别关键的是,这项研究为快速分离高效低毒的抗癌中草药提供了绝佳机会。

英文摘要:Tumor angiogenesis is a hallmark of cancer. Therapeutic drug inhibitors targeting angiogenesis are clinically effective. We have previously identified GT198 (gene symbol PSMC3IP, also known as Hop2) as an oncoprotein that induces tumor angiogenesis in human cancers, including oral cancer. In this study, we show that GT198 protein is a direct drug target of more than a dozen oncology drugs and several clinically successful anticancer herbs. GT198 is a DNA repair protein that binds to DNA. Using an in vitro DNA-binding assay, we tested the approved oncology drugs set VII from NCI containing 129 oncology drugs. Identified GT198 inhibitors include but are not limited to mitoxantrone, doxorubicin, paclitaxel, etoposide, dactinomycin, and imatinib. Paclitaxel and etoposide have higher binding affinities, whereas doxorubicin has higher binding efficacy due to competitive inhibition. GT198 shares protein sequence homology with DNA topoisomerases, which are known drug targets, so that GT198 is likely a new drug target previously unrecognized. To seek more powerful GT198 inhibitors, we further tested several anticancer herbal extracts. The positive anticancer herbs with high affinity and high efficacy are all clinical successful ones, including allspice from Jamaica, Gleditsia sinensis or honey locust from China, and BIRM from Ecuador. Partial purification of allspice using organic chemical approach demonstrated great feasibility of natural product purification, when the activity is monitored by the in vitro DNA-binding assay using GT198 as target. Together, our study reveals GT198 as a new targeting mechanism for existing oncology drugs. The study also delivers an excellent drug target suitable for compound identification and natural product purification. In particular, this study opens an opportunity to rapidly identify drugs with high efficacy and low toxicity from nature.

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[V2] 2021-07-12 21:11:28 chinaXiv:202107.00008V2 下载全文
[V1] 2021-07-08 22:17:05 chinaXiv:202107.00008v1 查看此版本 下载全文
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