A novel star-shaped trinuclear platinum() complex based on a 1,3,5-triazine core displaying potent antiproliferative activity against TNBC by the mitochondrial injury and DNA damage mechanism

• Published in: Dalton transactions : an international journal of inorganic chemistry 2022-07, Vol.51 (29), p.193-1942
• Main Authors: Wu, Yixuan, Zhao, Dandan, Shang, Jinting, Huang, Wenxin, Chen, Zhanfen
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antiproliferatives; Apoptosis; Cell cycle; Cytochromes; Damage; Depolarization; DNA damage; Drug resistance; Drugs; Flow cytometry; Flow resistance; Grooves; Membranes; Mitochondria; Monomers; Nuclei (cytology); Platinum; Side effects
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/d2dt00895e

Polynuclear platinum( ii ) complexes represent a class of great prospective Pt-based antitumor drugs that may expand the antitumor spectrum and overcome the clinical problems of drug resistance and side effects of platinum-based drugs. Herein, a novel star-shaped trinuclear platinum( ii ) complex [Pt 3 ( L -3H)Cl 3 ] ( 1 , L = 2,4,6-tris[(2-hydroxybenzyl)(2-pyridylmethyl)amine]-1,3,5-triazine) and its monomer [Pt( L′ -H)Cl] ( 2 , L′ = (2-hydroxybenzyl)(2-pyridylmethyl)amine) were synthesized and characterized. The in vitro antiproliferative activities of complexes 1 and 2 against a panel of human cancer cell lines including MDA-MB-231 (triple-negative breast cancer, TNBC), MCF-7 (breast), HepG-2 (liver), and A549 (lung) were investigated. The results revealed that 1 exhibited much higher antiproliferative properties than its monomer 2 against the tested cell lines. Importantly, 1 possessed 3.3-fold higher antiproliferative activity as compared with cisplatin against the TNBC cell line MDA-MB-231. Another TNBC cell line MDA-MB-468 is also sensitive to 1 . The results indicated that 1 might have the potential to act as a candidate for the treatment of TNBC. Cellular uptake and distribution studies showed that 1 could pass through the membrane of cells and enter into cells and mainly accumulate in the nuclei and mitochondria. 1 could bind to DNA in a cooperative groove-electrostatic-platinating binding mode and induce stronger DNA double-strand breaks (DSBs) and damaging effects on MDA-MB-231 than cisplatin (upregulation of γ-H2AX). Moreover, the DNA damage could not be easily repaired (upregulation of p53), which would exert a much positive influence on the overcoming of drug resistance. Additionally, flow cytometry studies showed that 1 arrested the cell cycle in the G0/G1 phase, induced mitochondrial membrane depolarization, increased ROS generation, and induced cell apoptosis. The results demonstrated that 1 could target simultaneously mitochondria and nuclei that gave rise to mitochondrial injury and DNA damage and ultimately efficiently promote the apoptotic death of tumor cells. Further mechanistic studies showed that 1 induced MDA-MB-231 cell apoptosis via the p53-mediated mitochondrial pathway by upregulating Bax and cytochrome c and downregulating Bcl-2 proteins, leading to the activation of caspase-3 and upregulation of the cleaved-PARP level. Taken together, 1 with such a synergic mechanism has great potential to be an effective anticancer agent t