Therapeutic Potential of Vanadium Complexes With 1,10-Phenanthroline Ligands, Quo Vadis? Fate of Complexes in Cell Media and Cancer Cells

Abstract

[Abstract] VⁱᵛO-complexes formulated as [VⁱᵛO(OSO₃)(phen)₂] (1) (phen = 1,10-phenanthroline), [VⁱᵛO(OSO₃)(Me₂phen)₂] (2) (Me₂phen = 4,7-dimethyl-1,10-phenanthroline) and [VⁱᵛO(OSO₃)(amphen)₂] (3) (amphen = 5-amino-1,10-phenanthroline) were prepared and stability in cell incubation media evaluated. Their cytotoxicity was determined against the A2780 (ovarian), MCF7 (breast) and PC3 (prostate) human cancer cells at different incubation times. While at 3 and 24 h the cytotoxicity differs for complexes and corresponding free ligands, at 72 h incubation all compounds are equally active presenting low IC₅₀ values. Upon incubation of A2780 cells with 1–3, cellular distribution of vanadium in cytosol, membranes, nucleus and cytoskeleton, indicate that the uptake of V is low, particularly for 1, and that the uptake pattern depends on the ligand. Nuclear microscopic techniques are used for imaging and elemental quantification in whole PC3 cells incubated with 1. Once complexes are added to cell culture media, they decompose, and with time most Vⁱᵛ oxidizes to Vᵛ-species. Modeling of speciation when [VⁱᵛO(OSO₃)(phen)₂] (1) is added to cell media is presented. At lower concentrations of 1, VⁱᵛO- and phen-containing species are mainly bound to bovine serum albumin, while at higher concentrations [VⁱᵛO(phen)ₙ]²⁺-complexes become relevant, being predicted that the species taken up and mechanisms of action operating depend on the total concentration of complex. This study emphasizes that for these VⁱᵛO-systems, and probably for many others involving oxidovanadium or other labile metal complexes, it is not possible to identify active species or propose mechanisms of cytotoxic action without evaluating speciation occurring in cell media.