阿霉素诱导乳腺癌细胞P-gp高表达的代谢性分子机理研究

项目名称： 阿霉素诱导乳腺癌细胞P-gp高表达的代谢性分子机理研究

项目编号： No.81503139

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 曹蓓

作者单位： 南京大学

项目金额： 17.9万元

中文摘要： 化疗药引起肿瘤耐药给临床肿瘤治疗带来了严峻挑战。研究证实肿瘤细胞常出现与众不同的代谢重排，前期研究显示: 以P-gp高表达为最显著特征的阿霉素耐药型乳腺癌细胞中阿霉素的细胞药代行为发生显著变化而极大贡献于耐药的发生；且其自身代谢模式也显著区别于敏感细胞，突出表现在耐药细胞中氨基酸和核酸的利用率减慢、谷胱甘肽循环异常而甘油代谢加快，但代谢重排与耐药之间的关系尚不清楚。项目计划在体外前期研究基础上，以代谢组学为基础在乳腺癌病人中初步探索阿霉素耐药表型的代谢特征和药物应答规律。借助于代谢通路、网络分析和药代-代谢组关联性分析等筛选出耐药相关的关键通路及标志物，并整合分子生物学和药代动力学研究手段予以证实。在此基础上考察调控代谢通路尤其是胱氨酸循环对阿霉素药效的影响。总之，本项目以代谢组学为导向，揭示与阿霉素耐药相关的代谢性分子机制，为解决化疗耐药难题和发现潜在增敏靶点提供依据。

中文关键词： 化疗耐药；机理研究；阿霉素；代谢组学；药物代谢动力学

英文摘要： Acquired resistance to chemotherapy drugs greatly challenged the treatment of cancer in clinical. Studies already demonstrated that profound metabolic reprogramming occurred in cancer cells, while our preliminary study suggested that adriamycin-resistant breast cancer cells, characterized by high expression of P-gp, have significantly altered pharmacokinetic behavior, which greatly contributed to the occurrence of drug resistance. Moreover, its own metabolic patterns were also distinctly different from the sensitive phenotype cells, especially retarded turnover of amino acids and nucleic acids, aberrant glutathione cycle and accelerated metabolism of glycerol. However, the relationship between the metabolic rearrangement and drug resistance remains unclear. Hence, on the basis of prvious studies in vitro, this proposal intends to further performe research on breast cancer patients sensitive or resistant breast cancer to adriamycin chemotherapy through metabolomics approach so as to clarify metabolic characteristics and metabolic response to adriamycin under the resistant phenotype. Biomarkers and key pathways closely associated with resistance will be screened and identified by metabolic pathways/network analysis, and further validated with molecular biology methods. We will also assess alterations in the efficacy of adriamycin after interference of metabolic pathways to seek potential targets for reversal of chemoresistance. In summary, combining metabolomics-informed targeted gene/protein investigation and pharmacokinetic-assisted study of adriamycin-resistant bio-system allowed for more comprehensive interrogation of mechanisms involved in the acquired resistance, which will be a solid support for the research of chemo-resistance and provide a new approach for the development of sensitizing agents.

英文关键词： chemoresistance;mechanism;adriamycin;metabolomics;pharmacokinetics