Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3β/Fyn pathway.

Abstract

Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3, RuIQ-4, and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5, were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo. Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3β/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity.

• Authors: Lanmei Chen, Jie Wang, Xianhong Cai, Suxiang Chen, Jingjing Zhang, Baojun Li, Weigang Chen, Xinhua Guo, Hui Luo, Jincan Chen
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 119 Pg. 105516 (02 2022) ISSN: 1090-2120 [Electronic] United States
• PMID: 34856444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Coordination Complexes
• FYB1 protein, human
• Isoquinolines
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Ruthenium
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• isoquinoline
• Cisplatin

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cisplatin (chemistry, pharmacology)
• Coordination Complexes (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, metabolism)
• Humans
• Isoquinolines (chemistry, pharmacology)
• Molecular Structure
• NF-E2-Related Factor 2 (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Ruthenium (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Zebrafish