State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences , Nanjing University , Nanjing 210023 , P.R. China.
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering , Nanjing University , Nanjing 210023 , P.R. China.
Inorg Chem. 2019 May 6;58(9):6507-6516. doi: 10.1021/acs.inorgchem.9b00708. Epub 2019 Apr 23.
Cancer is characterized by abnormal cellular energy metabolism, which preferentially switches to aerobic glycolysis rather than oxidative phosphorylation as a means of glucose metabolism. Many key enzymes involved in the abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV) complexes are potential anticancer prodrugs and kinetically more inert than the platinum(II) counterparts, which offer an opportunity to be modified by functional ligands for activation or targeted delivery. A novel platinum(IV) complex, c, c, t-[Pt(NH)Cl(CHNOS)(CHOCl)] (DPB), was designed to explore the effects of axial ligands on the reactivity and bioactivity of the complex as well as on tumor energy metabolism. The complex was characterized by electrospray ionization mass spectrometry and multinuclear (H, C, and Pt) NMR spectroscopy. The introduction of dichloroacetate (DCA) markedly increases the lipophilicity, reactivity, and cytotoxicity of the complex and blocks the growth of cancer cells having active glycolysis, and the introduction of biotin (CHNOS) enhances the tumor-targeting potential of the complex. The cytotoxicity of DPB is increased dramatically in a variety of cancer cell lines as compared with the platinum(IV) complex PB without the DCA group. DPB alters the mitochondrial membrane potential and disrupts the mitochondrial morphology. The levels of mitochondrial and cellular reactive oxygen species are also decreased. Furthermore, the mitochondrial function of tumor cells was impaired by DPB, leading to the inhibition of both glycolysis and glucose oxidation and finally to the death of cancer cells via a mitochondria-mediated apoptotic pathway. These findings demonstrate that DPB suppresses cancer cells mainly through altering metabolic pathways and highlight the importance of dual-targeting for the efficacy of anticancer drugs.
癌症的特征是细胞能量代谢异常，其优先转向有氧糖酵解，而不是氧化磷酸化作为葡萄糖代谢的一种手段。许多参与异常糖酵解的关键酶是潜在的抗癌药物靶点。铂(IV)配合物是潜在的抗癌前药，其动力学惰性比铂(II)对应物更强，这为通过功能配体进行修饰以实现激活或靶向递送提供了机会。一种新型的铂(IV)配合物 c, c, t-[Pt(NH)Cl(CHNOS)(CHOCl)] (DPB)，被设计用来探索轴向配体对配合物的反应性和生物活性以及对肿瘤能量代谢的影响。该配合物通过电喷雾电离质谱和多核（H、C 和 Pt）NMR 光谱进行了表征。引入二氯乙酸（DCA）显著增加了配合物的亲脂性、反应性和细胞毒性，并阻断了具有活跃糖酵解的癌细胞的生长，而生物素（CHNOS）的引入增强了配合物的肿瘤靶向潜力。与不含 DCA 基团的铂(IV)配合物 PB 相比，DPB 在多种癌细胞系中的细胞毒性显著增加。DPB 改变线粒体膜电位并破坏线粒体形态。线粒体和细胞内活性氧的水平也降低了。此外，DPB 还损害了肿瘤细胞的线粒体功能，导致糖酵解和葡萄糖氧化均受到抑制，最终通过线粒体介导的凋亡途径导致癌细胞死亡。这些发现表明 DPB 主要通过改变代谢途径来抑制癌细胞，并强调了双重靶向对抗癌药物疗效的重要性。
