黄葵总酮对大鼠顺铂化疗减毒增效作用机理的代谢组学研究

项目名称： 黄葵总酮对大鼠顺铂化疗减毒增效作用机理的代谢组学研究

项目编号： No.81503300

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： 李长印

作者单位： 南京中医药大学

项目金额： 18万元

中文摘要： 顺铂是当前肿瘤联合化疗的主流用药，但剂量限制性肾毒性，极大限制顺铂的临床应用。目前顺铂肾毒作用机理尚未完全明确，仍缺乏显著降低肾毒性且不影响化疗效果的保护剂。本课题组前期研究表明，中药黄蜀葵花提取物黄葵总酮（HKZT）可以有效缓解顺铂所致机体肾毒性；同时研究显示，金丝桃苷等黄葵中主要化学成分均具有明确的抗肿瘤活性。因此，本课题设想HKZT可作为理想的顺铂化疗保护剂。而代谢组学在阐明顺铂多重复杂致毒机理和HKZT多成分多靶点协同增效的整体药效方面具有独特优势。基于此，本研究拟从正常大鼠和荷瘤大鼠水平，采用基于RP/HILIC-UPLC-TOFMS的代谢组学研究手段，系统考察HKZT对顺铂肾毒性及其化疗疗效的影响，以期从代谢物组层面筛选顺铂致毒、HKZT减毒和增效相关生物标志物，揭示其内在作用机理。本课题可全面评价HKZT作为顺铂化疗肾保护剂的合理性，拓展黄葵制剂在肿瘤临床治疗中的应用。

中文关键词： 顺铂肾毒性；代谢组学；黄葵；减毒增效机理；液质联用

英文摘要： Cisplatin is one of the most widely used and most potent chemotherapy drugs. However, side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of cisplatin and related platinum-based therapeutics. The underlying mechanism of this nephrotoxicity has not fully understood, and there still lack of the effective renoprotective approaches without compromising the anti-tumour activity of cisplatin. Our preliminary study demonstrated that the total flavonoids extracted from flowers of Abelmoschus manihot (named as HKZT) could effectively attenuate cisplatin-induced nephrotoxicity. Moreover, most major constituents contained in HKZT were proved to possess remarkable anti-tumour activities. Accordingly, we proposed that HKZT has the potential to be an ideal renoprotective preparation for cisplatin-induced nephrotoxicity. Metabonomic approaches has unique advantages in elucidating the complex multi-pathway mechanisms of cisplatin-induced nephrotoxicity, and characterizing the holistic pharmacological properties of HKZT displayed as multi-component, multi-target and multi-pathway. Considering this, in the current project, an RP/HILIC-UPLC-TOFMS metabonomic approach is employed to investigate the evolution process of cisplatin-induced nephrotoxicity, the renoprotective action of HKZT on the nephrotoxicity, as well as the effect of HKZT on the anti-tumour activity of cisplatin, in normal and tumor-bearing rats, thereby screening the metabolite-level biomarkers to elucidate the mechanism of nephrotoxicity, renoprotection and chemotherapy enhancement. This project would fully demonstrate the feasibility of using HKZT as an ideal renoprotection for cisplatin-based therapy, providing the scientific basis to support the application of HKZT-related prescriptions in clinical cancer therapy.

英文关键词： cisplatin-induced nephrotoxicity;metabonomics;Huangkui; mechanism of toxicity-attenuation and chemotherapy-enhancement ;RP/HILIC-UPLC-TOFMS