Mitochondria-targeting monofunctional platinum(ii)–lonidamine conjugates for cancer cell de-energization. Issue 20 (21st September 2020)

• Record Type: Journal Article
• Authors: Muhammad, Nafees; Tan, Cai-Ping; Muhammad, Kamran; Wang, Jie; Sadia, Nasreen; Pan, Zheng-Yin; Ji, Liang-Nian; Mao, Zong-Wan
• Is Part Of: Inorganic chemistry frontiers. Volume 7:Issue 20(2020)
• Page Start: 4010
• Page End: 4019
• Publication Date: 2020-09-21
• Subjects: Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/d0qi01028f
• Languages: English
• ISSNs: 2052-1553

Abstract

Abstract : We report the rational design and anticancer mechanism studies of novel mitochondria-targeting monofunctional Pt(ii )–lonidamine conjugates for the selective de-energization of cancer cells. Abstract : Monofunctional Pt(ii ) complexes represent a class of antitumor agents that may expand the antitumor spectrum and overcome the drug resistance of the clinically used cisplatin and its derivatives. Herein, we designed three novel monofunctional Pt(ii ) complexes, namely, MPL-I, MPL-II and MPL-III, by anchoring lonidamine (an inhibitor of mitochondrial hexokinase) to the Pt(ii ) centre for the selective de-energization of cancer cells. Among them, MPL-III is more potent than cisplatin against triple negative breast cancer MDA-MB-231 cells and exhibits relatively lower cytotoxicity on breast epithelial cells. Intracellular distribution studies reveal that MPL-III mainly accumulates in the mitochondria. Furthermore, MPL-III induces detrimental changes in the mitochondrial ultrastructure and significant loss of the mitochondrial membrane potential, inhibits glycolysis and disrupts mitochondrial respiration. As a consequence, MPL-III causes cell cycle arrest in the G0/G1 phase, and mitochondria-mediated apoptosis involving caspase activation and cytochrome c release. RNA-sequencing data show that MPL-III perturbs the pathways including DNA damage, metabolic process and transcription regulator activity. Our research provides an in-depth study and a new design strategy for effective mono-functional platinum complexes with action mechanisms distinct from those of the clinical platinum-based anticancer drugs.