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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

Levina, Aviva, McLeod, Andrew I., Pulte, Anna, Aitken, Jade B., and Lay, Peter A.. Biotransformations of antidiabetic vanadium prodrugs in mammalian cells and cell culture media: A XANES spectroscopic study. United States: N. p., Web. doi:10.1021/ic5028948.
Levina, Aviva, McLeod, Andrew I., Pulte, Anna, Aitken, Jade B., & Lay, Peter A.. Biotransformations of antidiabetic vanadium prodrugs in mammalian cells and cell culture media: A XANES spectroscopic study. United States. doi:10.1021/ic5028948.
Levina, Aviva, McLeod, Andrew I., Pulte, Anna, Aitken, Jade B., and Lay, Peter A.. 2015. "Biotransformations of antidiabetic vanadium prodrugs in mammalian cells and cell culture media: A XANES spectroscopic study". United States. doi:10.1021/ic5028948. https://www.osti.gov/servlets/purl/1347219.
@article{osti_1347219,
title = {Biotransformations of antidiabetic vanadium prodrugs in mammalian cells and cell culture media: A XANES spectroscopic study},
author = {Levina, Aviva and McLeod, Andrew I. and Pulte, Anna and Aitken, Jade B. and Lay, Peter A.},
abstractNote = {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 ([VVO4]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% VIV 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 VV reduction to VIV occurred predominantly in the cytoplasm, while accumulation of VV in the nucleus was likely to have been facilitated by noncovalent bonding to histone proteins. The nuclear VV 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 VIV species, despite the prevalence of VV 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.},
doi = {10.1021/ic5028948},
journal = {Inorganic Chemistry},
number = 14,
volume = 54,
place = {United States},
year = {2015},
month = {4}
}