A novel star-shaped trinuclear platinum(ii) complex based on a 1, 3, 5-triazine core displaying potent antiproliferative activity against TNBC by the mitochondrial injury and DNA damage mechanism. Issue 29 (22nd June 2022)

• Record Type: Journal Article
• Authors: Wu, Yixuan; Zhao, Dandan; Shang, Jinting; Huang, Wenxin; Chen, Zhanfen
• Is Part Of: Dalton transactions. Volume 51:Issue 29(2022)
• Page Start: 10930
• Page End: 10942
• Publication Date: 2022-06-22
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/d2dt00895e
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : A novel trinuclear platinum(ii ) complex could target simultaneously mitochondria and nuclei, induce mitochondrial injury and DNA damage, and ultimately promote the apoptotic death of TNBC. Abstract : 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 [Pt3 (L –3H)Cl3 ] (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 that can overcome treatment resistance in TNBC.