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Title: Biotransformations of antidiabetic vanadium prodrugs in mammalian cells and cell culture media: A XANES spectroscopic study

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 ([V VO 4] 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), -(IV), and -(III) complexes. Both A and B ([V] = 1.0 mM) gradually converged into similar mixtures of predominantly five- and six-coordinate VV species (~75% total V) in a cell culture medium within 24 h at 310 K. Speciation of V in intact HepG2 cells also changed with the incubation time (from ~20% 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 ofmore » 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. Lastly, 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.« less
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1]
  1. The Univ. of Sydney, Sydney, NSW (Australia)
Publication Date:
Grant/Contract Number:
DP0208409; DP0774173; DP0984722; DP1095310; DP130103566; LE0346515
Type:
Accepted Manuscript
Journal Name:
Inorganic Chemistry
Additional Journal Information:
Journal Volume: 54; Journal Issue: 14; Journal ID: ISSN 0020-1669
Publisher:
American Chemical Society (ACS)
Research Org:
Univ. of Sydney, Syndey, NSW (Australia)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States); Australian Research Council (ARC) (Australia)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1347219