新型丹参素衍生物通过调控线粒体生物合成保护阿霉素心脏毒性的机制研究

Doxorubicin (Dox) is an anthracycline antibiotic widely used in clinics as an anticancer agent. However, the use of Dox is limited by its cardiotoxicity. D006, a novel agent with strong cardioprotective effect, has been synthesized. We found D006 was more potent than either parental compound, or their use in combination, in ameliorating Dox-induced toxicity in H9c2 cells. In zebrafish model, D006 significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, D006 upregulated mitochondrial biogenesis after Dox treatment in H9c2 cells. We found D006 derivative BAA may bind to ERP57 protein in rat platelet and inhibit its activity. BAA can also bind to ERP57 protein in H9c2 cells. Whether D006 promotes mitochondrial biogenesis through the inhibition of ERP57 is still unknown. In this study, we further investigate the mechanisms underlying the cardioprotective effects of D006 by working on ERP57 pathway and using small molecular probe. This study will provide new strategies for developing novel drugs for the treatment of Dox cardiotoxicity.

阿霉素作为广谱抗癌药物在临床上被广泛应用，然而阿霉素的心脏毒性严重限制其临床使用。我们前期合成并筛选出具有强心脏保护活性的丹参素衍生物D006，研究表明，D006可以保护阿霉素诱导的H9c2细胞损伤和斑马鱼心脏毒性，D006的心脏保护作用与其促进线粒体生物合成有关，但D006促进线粒体生物合成的机制尚不清楚。前期研究发现连有生物素的D006衍生物BAA可以从大鼠血小板蛋白中“钓取”靶蛋白ERP57并抑制其活性，BAA也可以与H9c2内ERP57蛋白结合，D006是否通过靶向ERP57促进线粒体生物合成有待于进一步研究。本课题将通过研究ERP57过表达和沉默后对D006心脏保护作用及促进线粒体生物合成影响，并利用小分子探针“钓取”靶标蛋白的方法，阐明D006促进线粒体生物合成保护阿霉素心脏毒性的机制，为开发新型抗阿霉素心脏毒性药物提供理论基础。

阿霉素作为广谱抗癌药物在临床上被广泛应用，然而阿霉素的心脏毒性严重限制其临床使用。我们前期合成并筛选出具有心脏保护活性的丹参素衍生物DT-010，研究表明，DT-010可以促进线粒体生物合成、保护阿霉素诱导线粒体形态改变、保护氧化应激损伤和保护阿霉素诱导斑马鱼心脏毒性。但DT-010促进线粒体生物合成保护阿霉素心脏毒性机制尚不清楚。本研究进一步通过蛋白组学方法结合western blot等方法，阐释了DT-010可以通过调节NCAM1蛋白，调节Sirt1/PGC-1a/HO-1线粒体生物合成通路，起到抗氧化和保护阿霉素诱导心脏毒性作用。NCAM1蛋白有望作为抗阿霉素心脏毒性靶点，为后续基础研究及药物开发奠定基础。