Effect of the extra-nuclear cation on the cytotoxicity and mechanism of action of pyridine-2,6-dicarboxylate Ga(III) complexes

Abstract

Two Ga(III) complexes (C1) and (C2) were prepared by the one-pot reaction of pyridine-2,6-dicarboxylic acid and aminopyridine derivatives with gallium(III) nitrate octahydrate. The compounds were characterized by single-crystal X-ray diffraction. The distorted octahedral geometry was confirmed by crystallographic data for both complexes. The study of the in vitro cytotoxicity of the compounds showed that the presence of different extra-nuclear cations can affect the cytotoxicity of the same anionic complexes. The most significant antiproliferative activity was observed for C1 (IC50 = 0.69 μM, MAE = 73.96%) and C2 (IC50 = 3.78 μM, MAE = 60.35%) (where MAE represents the maximal antiproliferative effect) against A431 cell line. The mechanistic study evidenced the same pathway for the death of A431 cells treated with the complexes, although the results for C2 were obtained at approximately five times the concentration of C1. According to the study, both complexes induced cell cycle arrest in G2/M phase in A431 cells by upregulating the levels of p21, p27, p-cdc25C, and p-cdc2 and downregulating the levels of cdc25C, cdc2, and cyclin B1. In addition, apoptosis via a caspase-dependent mitochondrial pathway was confirmed by a decrease in Bcl-2 family proteins and an increase in the expression of procaspase-9 and 3. Also, the complexes induced autophagic cell death by activating the RAGE /PI3KC3/Beclin 1 pathway in A431 cells. Data availabilityCCDC 874052 and 874055 contain the supplementary crystallographic data for C1 and C2, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/services/structures?pid=ccdc:874052,874055&sid=CCDCManual, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223–336–033; or e-mail: deposit@ccdc.cam.ac.uk.