Journal
INORGANIC CHEMISTRY
Volume 54, Issue 14, Pages 6707-6718Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ic5028948
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Funding
- Australian Research Council (ARC) [DP0208409, DP0774173, DP0984722, DP1095310, DP130103566]
- ARC [DP0208409, DP0984722]
- ARC LIEF grant [LE0346515]
- Commonwealth of Australia under the Major National Research Facilities program
- National Institutes of Health, National Center for Research Resources, Biomedical Technology Program
- Department of Energy, Office of Biological and Environmental Research
- ASRP
- Australian Research Council [LE0346515, DP0208409, DP0774173, DP1095310] Funding Source: Australian Research Council
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The antidiabetic activities of vanadium(V) and -(IV) prodrugs are determined by their ability to release active species upon interactions with components of biological media. The first X-ray absorption spectroscopic study of the reactivity of typical vanadium (V) antidiabetics, vanadate ([(VO4)-O-V](3-), A) and a vanadium(IV) bis(maltolato) complex (B), with mammalian cell cultures has been performed using HepG2 (human hepatoma), A549 (human lung carcinoma), and 3T3-L1 (mouse adipocytes and preadipocytes) cell lines, as well as the corresponding cell culture media. X-ray absorption near-edge structure data were analyzed using empirical correlations with a library of model vanadium(V), and -(III) complexes. Both A and B ([V] = 1.0 mM) gradually converged into similar mixtures of predominantly five- and six-coordinate V-V species (similar to 75% total V) in a cell culture medium within 24 h at 310 K. Spedation of V in intact HepG2 cells also changed with the incubation time (from similar to 20% to similar to 70% V-IV of total V), but it was largely independent of the prodrug used (A or B) or of the predominant V oxidation state in the medium. Subcellular fractionation of A549 cells suggested that V-V reduction to V-IV occurred predominantly in the cytoplasm, while accumulation of V-V in the nucleus was likely to have been facilitated by noncovalent bonding to histone proteins. The nuclear V-V is likely to modulate the transcription process and to be ultimately related to cell death at high concentrations of V, which may be important in anticancer activities. Mature 3T3-L1 adipocytes (unlike for preadipocytes) showed a higher propensity to form V-IV species, despite the prevalence of V-V in the medium. The distinct V biochemistry in these cells is consistent with their crucial role in insulin-dependent glucose and fat metabolism and may also point to an endogenous role of V in adipocytes.
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