State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, Guangxi, China.
Molecules. 2019 Jul 12;24(14):2544. doi: 10.3390/molecules24142544.
Multi-targeting of oncoproteins by a single molecule represents an effectual, rational, and an alternative approach to target therapy. We carried out a systematic study to reveal the mechanisms of action of newly synthesized Cu compounds of 2-naphthalenol and 1-(((2-pyridinylmethyl)imino)methyl)- (C1 and C2). The antiproliferative activity of the as-synthesized complexes in three human cancer cell lines indicates their potential as multi-targeted antitumor agents. Relatively, C1 and C2 showed better efficacy in vitro relative to Cisplatin and presented promising levels of toxicity against A-549 cells. On the whole, the Cu complexes exhibited chemotherapeutic effects by generating reactive oxygen species (ROS) and arresting the cell cycle in the G/G phase by competent regulation of cyclin and cyclin-dependent kinases. Fascinatingly, the Cu complexes were shown to activate the apoptotic and autophagic pathways in A-549 cells. These complexes effectively induced endoplasmic reticulum stress-mediated apoptosis, inhibited topoisomerase-1, and damaged cancer DNA through a ROS-mediated mechanism. The synthesized Cu complexes established ROS-mediated targeting of multiple cell signaling pathways as a fabulous route for the inhibition of cancer cell growth.
单一分子对癌蛋白的多靶向作用代表了一种有效的、合理的、替代的靶向治疗方法。我们进行了一项系统的研究，以揭示新合成的 2-萘酚和 1-(((2-吡啶基甲基)亚氨基)甲基)-（C1 和 C2）的铜化合物的作用机制。所合成的配合物在三种人癌细胞系中的抗增殖活性表明它们具有作为多靶点抗肿瘤剂的潜力。相对而言，C1 和 C2 在体外比顺铂更有效，并且对 A-549 细胞表现出有希望的毒性水平。总的来说，铜配合物通过产生活性氧（ROS）和通过调节细胞周期蛋白和细胞周期蛋白依赖性激酶使细胞周期停滞在 G1/G0 期来发挥化学治疗作用。有趣的是，铜配合物被证明能够在 A-549 细胞中激活凋亡和自噬途径。这些配合物通过 ROS 介导的机制有效地诱导内质网应激介导的凋亡，抑制拓扑异构酶-1，并通过 ROS 介导的机制损伤癌细胞 DNA。合成的铜配合物建立了 ROS 介导的多种细胞信号通路的靶向作用，作为抑制癌细胞生长的极好途径。
