Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis

Hong Tang; Xinhua Guo; Wenzhu Yu; Jie Gao; Xufeng Zhu; Zunnan Huang; Wenhui Ou; Hanfu Zhang; Lanmei Chen; Jincan Chen

doi:10.1016/j.jinorgbio.2023.112295

Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis

J Inorg Biochem. 2023 Sep:246:112295. doi: 10.1016/j.jinorgbio.2023.112295. Epub 2023 Jun 15.

Authors

Hong Tang¹, Xinhua Guo², Wenzhu Yu¹, Jie Gao³, Xufeng Zhu⁴, Zunnan Huang⁵, Wenhui Ou⁶, Hanfu Zhang⁷, Lanmei Chen⁸, Jincan Chen⁹

Affiliations

¹ Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong 524023, PR China.
² Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China.
³ Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong 524023, PR China.
⁴ The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong 524023, PR China.
⁵ Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; Key Laboratory of Computer-Aided Drug Design of Dongguan City, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China.
⁶ Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China.
⁷ School of Molecular Science, The University of Western Australia, Perth 6009, WA, Australia.
⁸ Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; Key Laboratory of Computer-Aided Drug Design of Dongguan City, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China. Electronic address: chenlanmei@gdmu.edu.cn.
⁹ The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong 524023, PR China; Key Laboratory of Computer-Aided Drug Design of Dongguan City, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China. Electronic address: chenjc@gdmu.edu.cn.

PMID: 37348172
DOI: 10.1016/j.jinorgbio.2023.112295

Abstract

Two new ruthenium(II) complexes [Ru(dip)₂(PPβC)]PF₆ (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPβC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)₂(PPβC)]PF₆ (Ru2, phen = 1, 10-phenanthroline) with β-carboline derivative PPβC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC₅₀ values ranging from 0.5 to 3.6 μM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.

Keywords: Anticancer; Apoptosis; Mitochondria; Ru(II) complexes; Topoisomerase I; β-carboline derivative.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Antineoplastic Agents* / metabolism
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Coordination Complexes* / metabolism
Coordination Complexes* / pharmacology
DNA, Mitochondrial / metabolism
DNA, Mitochondrial / pharmacology
Humans
Mitochondria / metabolism
Reactive Oxygen Species / metabolism
Ruthenium* / metabolism
Ruthenium* / pharmacology

Substances

Ruthenium
Antineoplastic Agents
DNA, Mitochondrial
Coordination Complexes
Reactive Oxygen Species