6-Methoxyquinoline complexes as lung carcinoma agents: induction of oxidative damage on A549 monolayer and multicellular spheroid model

Abstract

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.

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Funding

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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Cadavid-Vargas, J.F., Villa-Pérez, C., Ruiz, M.C. et al. 6-Methoxyquinoline complexes as lung carcinoma agents: induction of oxidative damage on A549 monolayer and multicellular spheroid model. J Biol Inorg Chem 24, 271–285 (2019). https://doi.org/10.1007/s00775-019-01644-7

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Keywords

  • 6-Methoxyquinoline complexes
  • Lung carcinoma
  • A549 cells
  • Multicellular spheroid model
  • Oxidative damage