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

CADAVID-VARGAS, J. F.; VILLA-PÉREZ, C.; RUIZ, M. C.; LEÓN, I. E.; VALENCIA-URIBE, G. C.; SORIA, D. B.; ETCHEVERRY, S. B.; DI VIRGILIO, A. L.

JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY

SPRINGER

Lugar: Berlin; Año: 2019

0949-8257

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; theCo(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) andAg(I) complexes with a lower IC50(57.9 μM) in A549 cells exposed for 24 h. Cu6MQ decreased cell proliferation andinduced oxidative stress detected with H2DCFDAat 40 μM, which reduces GSH/GSSG ratio. This redox imbalance inducedoxidative DNA damage revealed by the Micronucleus test and the Comet assay, which turned into a cell cycle arrest at G2/Mphase and induced apoptosis. In multicellular spheroids, the IC50values tripled the monolayer model (187.3 μM for 24 h). Atthis concentration, the proportion of live/dead cells diminished, and the spheroids could not proliferate or invade. AlthoughZn6MQ also decreased GSH/GSSG ratio from 200 μM and the cytotoxicity is related to oxidative stress, the induction of thehydrogen peroxide levels only doubled the control value. Zn6MQ induced S phase arrest, which relates with the increasedmicronucleus frequency and with the induction of necrosis. Finally, our results reveal a synergistic activity with a 1:1 ratioof both complexes in the monolayer and multicellular spheroids.