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

L. Chen; J. Wang; X. Cai; S. Chen; J. Zhang; B. Li; W. Chen; X. Guo; H. Luo; J. Chen

doi:10.1016/j.bioorg.2021.105516

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

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

L. Chen, J. Wang, X. Cai, S. Chen, J. Zhang, B. Li, W. Chen, X. Guo, H. Luo and J. Chen

Bioorganic Chemistry, Vol.119, Art. 105516

2022

DOI: https://doi.org/10.1016/j.bioorg.2021.105516

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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.

Details

Title: Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3β/Fyn pathway
Authors/Creators: L. Chen (Author/Creator) - Guangdong Medical College
J. Wang (Author/Creator) - Guangdong Medical College
X. Cai (Author/Creator) - Guangdong Medical College
S. Chen (Author/Creator) - Murdoch University
J. Zhang (Author/Creator) - Guangdong Medical College
B. Li (Author/Creator) - Guangdong Medical College
W. Chen (Author/Creator) - Guangdong Medical College
X. Guo (Author/Creator) - Guangdong Medical College
H. Luo (Author/Creator) - Guangdong Medical College
J. Chen (Author/Creator) - Guangdong Medical College
Publication Details: Bioorganic Chemistry, Vol.119, Art. 105516
Publisher: Elsevier
Identifiers: 991005540676907891
Copyright: © 2021 Elsevier Inc.
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 2 Chemistry; 2.22 Inorganic & Nuclear Chemistry; 2.22.798 Metal Anticancer Complexes
Web Of Science research areas: Biochemistry & Molecular Biology; Chemistry, Organic
ESI research areas: Biology & Biochemistry