PUBLICATION
Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3β/Fyn pathway
- Authors
- Chen, L., Wang, J., Cai, X., Chen, S., Zhang, J., Li, B., Chen, W., Guo, X., Luo, H., Chen, J.
- ID
- ZDB-PUB-211203-5
- Date
- 2021
- Source
- Bioorganic chemistry 119: 105516 (Journal)
- Registered Authors
- Zhang, Jingjing
- Keywords
- Akt/GSK-3β/Fyn, Cisplatin resistance, Cyclometalated Ru(II)-isoquinoline complexes, Nrf2
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/antagonists & inhibitors
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Apoptosis/drug effects
- Cell Cycle Checkpoints/drug effects
- Cell Proliferation/drug effects
- Cisplatin/chemistry
- Cisplatin/pharmacology*
- Coordination Complexes/chemical synthesis
- Coordination Complexes/chemistry
- Coordination Complexes/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
- Glycogen Synthase Kinase 3 beta/metabolism
- Humans
- Isoquinolines/chemistry
- Isoquinolines/pharmacology*
- Molecular Structure
- NF-E2-Related Factor 2/antagonists & inhibitors
- NF-E2-Related Factor 2/metabolism
- Proto-Oncogene Proteins c-akt/antagonists & inhibitors
- Proto-Oncogene Proteins c-akt/metabolism
- Ruthenium/chemistry
- Ruthenium/pharmacology*
- Structure-Activity Relationship
- Tumor Cells, Cultured
- Zebrafish
- PubMed
- 34856444 Full text @ Bioorg. Chem.
Citation
Chen, L., Wang, J., Cai, X., Chen, S., Zhang, J., Li, B., Chen, W., Guo, X., Luo, H., Chen, J. (2021) Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3β/Fyn pathway. Bioorganic chemistry. 119:105516.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping