线粒体靶向性铜配合物通过SIRT3调控肝癌细胞自噬介导线粒体凋亡的作用及分子机制研究

It has been a hotspot in Anti tumor drug research to find complexes with high anti-cancer activities, low toxicities and weak resistance. The research of mitochondrial targeting copper complex is an effective strategy. Our group previously studied the design, synthesis, and antitumor activity of Triphenylphosphine-targeted copper complex CTB, and demonstrated that it carried evident mitochondria-targeted ability and strong anti-cancer activity. However, the underlying mechanisms need further study. Combined with the literature research, this project creatively proposes that CTB could exert anti-cancer effects through modulating autophagy-induced hepatocellular carcinoma cell mitochondrial apoptosis via SIRT3. Therefore, in whole, cell and molecular level, this project first study the mitochondrial pathway of CTB induced apoptosis in hepatocellular carcinoma cells, and then explain whether it can be modulated by autophagy. On this basis, we will explore the key role of SIRT3 in vivo and vitro experiment. Then we will reveal the anti-cancer molecular mechanisms of CTB, to provide theoretical basis for mitochondrial-targeted drug design in the future.

寻找活性强、毒性低、能克服抗药性的配合物药物一直是抗肿瘤药物研究的热点，线粒体靶向性铜配合物的研究是一个有效策略。课题组前期设计并合成了以三苯基膦（TPP）为靶向基团的铜(Ⅱ)配合物[Cu(ttpy-tpp)Br2]Br（以CTB表示），研究发现其具有明显的线粒体靶向能力和较强的抗肿瘤活性，但机制亟需深入研究。本项目创新性地提出CTB的抗肿瘤作用可能是通过SIRT3调控肝癌细胞自噬介导的线粒体凋亡这一机制。为此，本项目拟在整体、细胞与分子水平，研究CTB诱导肝癌细胞线粒体凋亡与自噬的相关性，阐明CTB通过自噬介导线粒体凋亡的作用机制，并通过体内外实验探究SIRT3在此机制中所起的关键作用，以此综合揭示CTB抗肿瘤的分子机制，为今后线粒体靶向性药物分子的设计及临床应用提供理论依据。

寻找活性强、毒性低、能克服抗药性的配合物药物一直是抗肿瘤药物研究的热点，线粒体靶向性铜配合物的研究是一个有效策略。课题组前期设计并合成了以三苯基膦（TPP）为靶向基团的铜(Ⅱ)配合物[Cu(ttpy-tpp)Br2]Br（以CTB表示），研究发现其具有明显的线粒体靶向能力和较强的抗肿瘤活性，但机制亟需深入研究。为此，本项目在整体、细胞与分子水平，明确线粒体靶向性铜配合物CTB通过调控肝癌细胞自噬介导线粒体凋亡作用及分子机制。研究结果如下：（1）CTB具有抑制肝癌细胞增殖及肿瘤组织生长的作用；（2）CTB诱导肝癌细胞线粒体功能障碍同时通过ROS依赖性的p53线粒体转位诱导线粒体凋亡；（3）CTB诱导肝癌细胞自噬同时通过Drp1依赖性线粒体分裂促进线粒体自噬；（4）自噬能够促进CTB对凋亡的诱导，同时CTB诱导的p53依赖性细胞凋亡受到Drp1依赖性细胞自噬的调控；（5）CTB通过调控Sirt3介导自噬的发生。这些发现从线粒体凋亡与自噬两个方面揭示了CTB对肝细胞癌的抗肿瘤效应并阐明其作用的分子机理，为今后线粒体靶向性配合物药物的设计及临床应用提供理论依据。