In vitro study of the pro-apoptotic mechanism of amino acid Schiff base copper complexes on anaplastic thyroid cancer
Peiran Zhao, Xinyan Zhang, Jianfang Dong, Lianzhi Li, Xiao Chen Meng, Lei Gao
Abstract
• Three five-coordinated polyhedron amino acid Schiff base copper (II) complexes were designed and characterized as potential anti-tumor drugs in this research. • Complex 1 exhibits excellent cytotoxicity with IC 50 values of 0.59±0.05 μM, 2.36±0.47 μM, 1.24±0.11 μM, 0.75±0.09 μM, 1.72±0.06 μM towards five thyroid cancer cell lines. • Complex 1 can effectively inhibit cancer cell growth mainly through mitochondrial dysfunction, intracellular ROS accumulation, and ROS-mediated DNA damage. • Complex 1 may induce apoptosis in ARO cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays excellent antitumor activity. In the endocrine system, anaplastic thyroid cancer (ATC) is extremely aggressive since it inhibits the majority of medications and treatments. Therefore, there is an immediate demand to identify new treatment approaches or drugs to deal with ATC. Recently, amino acid Schiff base copper complexes have received great attention due to their excellent anti-tumor activity. In this research, three copper(II) complexes, [Cu( o -van-D-Trp)(phen)] (1) , [Cu( o -van-D-Trp)(bipy)] (2) , [Cu(naph-D-Trp)(bipy)] (3) , [D-Trp = D-tryptophan; o-van = o -vanillin; naph = 2‑hydroxy-1- naphthaldehyde; phen = 1,10-phenanthroline; bipy = 2,2-biprydine], have been synthesized and investigated as potential anticancer agents. The crystal structure data of the complexes demonstrate that the central copper (II) atom forms a twisted polyhedral environment with nitrogen and oxygen atoms. The MTT results demonstrated that three complexes exhibited superior cytotoxicity against five cell lines of thyroid cancer (Cal-62 cells, ARO cells, KHM-5 m cells, BHP10–3 cells and K1 cells), especially complex 1 with the IC 50 values of 0.59±0.05 μM, 2.36±0.47 μM, 1.10±0.87 μM, 0.75±0.09 μM, 1.72±0.06 μM, when cisplatin was used as a control. Research on antitumor mechanisms has demonstrated that complex 1 can significantly reduce the mitochondrial membrane potential, raise autophagy, and produce reactive oxygen species (ROS) in ARO cells in a dose-dependent manner. RNA sequencing study reveals that complex 1 may cause apoptosis in ARO cells and exhibit anticancer efficacy in vitro through ROS-mediated downregulation of Akt and p38 MAPK activation.