6-Methoxyquinoline complexes as lung carcinoma agents: induction of oxidative damage on A549 monolayer and multicellular spheroid model
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The aim of this work was to study the antitumor effects and the mechanisms of toxic action of a series of 6-methoxyquinoline (6MQ) complexes in vitro. The Cu(II) and Zn(II) complexes (Cu6MQ and Zn6MQ) are formulated as M(6MQ)2Cl2; the Co(II) and Ag(I) compounds (Co6MQ and Ag6MQ) are ionic with formulae [Ag(6MQ)2]+NO3− and H(6MQ)+[Co(6MQ)Cl3]− (where H(6MQ)+ is the protonated ligand). We found that the copper complex, outperformed the Co(II), Zn(II) and Ag(I) complexes with a lower IC50 (57.9 µM) in A549 cells exposed for 24 h. Cu6MQ decreased cell proliferation and induced oxidative stress detected with H2DCFDA at 40 µM, which reduces GSH/GSSG ratio. This redox imbalance induced oxidative DNA damage revealed by the Micronucleus test and the Comet assay, which turned into a cell cycle arrest at G2/M phase and induced apoptosis. In multicellular spheroids, the IC50 values tripled the monolayer model (187.3 µM for 24 h). At this concentration, the proportion of live/dead cells diminished, and the spheroids could not proliferate or invade. Although Zn6MQ also decreased GSH/GSSG ratio from 200 µM and the cytotoxicity is related to oxidative stress, the induction of the hydrogen peroxide levels only doubled the control value. Zn6MQ induced S phase arrest, which relates with the increased micronucleus frequency and with the induction of necrosis. Finally, our results reveal a synergistic activity with a 1:1 ratio of both complexes in the monolayer and multicellular spheroids.
Keywords6-Methoxyquinoline complexes Lung carcinoma A549 cells Multicellular spheroid model Oxidative damage
This work was supported by UNLP (11X/690, PPID 2018/X032), CONICET (PIP 0034) and ANPCyT (PICT 2014-2223 and PICT 2016-0508) from Argentina.
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Conflict of interest
The authors confirm that they have no conflict of interest with the content of this article.
This article does not contain studies with human participants or animals performed by any of the authors.
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