Speciation, Protein Binding, Biotransformation, and Cytotoxicity of a VV–Lactate Complex

Abstract

We studied the speciation, protein binding, biotransformation, and cytotoxicity of the dioxidovanadium(V) lactate complex Cs2[VV2O4(lact)2]·2H2O and compared the results with those obtained for the analogous malate compound. 51V NMR and ESI-MS results show that Cs2[VV2O4(lact)2]·2H2O forms [VVO2]+, [H2VVO4]−, [H2VV2O7]2–, [VV2O4(lact)2]2–, [VV3O7(lact)2]3–, [VV4O12]4–, [VV5O15]5–, [VVO2(lact)(H2O)]−, [VVO2(lact)(OH)]2–, and [VV10O28]6– species in aqueous solution. In the presence of lysozyme, the amounts of [VV10O28]6– and [VVO2(lact)(H2O)]− significantly decrease and protein adducts with [VV2O4(lact)2]2– and [VVO(lact)2]− are detected by ESI-MS. X-ray structures of the adducts show noncovalent binding of [VIVO]2+, [VVO2]+, [VV2O4(lact)2]2–, cyclic [VV3O9]3–, and [VV3O7(lact)2]3– to lysozyme. Cs2[VV2O4(lact)2]·2H2O and Cs2[VV2O4(mal)2]·2H2O exhibit higher cytotoxicity than cisplatin on PC-3 cancer cells (IC50 values are 5.9 ± 0.3 and 5.0 ± 0.3 μM, respectively), while they are less active than cisplatin against HeLa cells and less selective against BALB/c-3T3 and HaCaT cells. In systems containing [VV2O4(lact)2]2– and biological reductants, EPR studies demonstrate the formation of hydroxyl radicals, supporting a mechanism in which redox cycling between VV and VIV contributes to the oxidative stress that accounts for the observed biological activity.