Metabolism of the tumor angiogenesis inhibitor 4-(N-(S-Glutathionylacetyl)amino)phenylarsonous acid

The Journal of Biological Chemistry
Pierre J DildaPhilip J Hogg

Abstract

4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) is a small, synthetic mitochondrial poison that targets angiogenic endothelial cells and is currently being tested in a Phase I/IIa clinical trial. The trivalent arsenical of GSAO reacts with and perturbs adenine nucleotide translocase of the inner mitochondrial membrane of endothelial cells, which leads to proliferation arrest. Three observations indicated that the gamma-glutamyl residue of GSAO is cleaved at the endothelial cell surface by gamma-glutamyl transpeptidase (gammaGT). GSAO was found to be an efficient substrate for gammaGT, endothelial cell accumulation and antiproliferative activity of GSAO was blunted by a competitive substrate and an active site inhibitor of gammaGT, and the level of cell surface gammaGT correlated strongly with the sensitivity of cells to GSAO. Using transport inhibitors, it was revealed that the resulting metabolite of GSAO cleavage by gammaGT, 4-(N-(S-cysteinylglycylacetyl)amino) phenylarsonous acid (GCAO), was transported across the plasma membrane by an organic anion transporter. Furthermore, GCAO is likely processed by dipeptidases in the cytosol to 4-(N-(S-cysteinylacetyl)amino) phenylarsonous acid (CAO), and it is this metabol...Continue Reading

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Citations

Oct 22, 2013·Cancer Chemotherapy and Pharmacology·Laura HorsleyUNKNOWN Cancer Research UK Drug Development Office Phase I clinical trial
Sep 16, 2011·Pharmaceutical Research·Emma E RamsayPierre J Dilda
Feb 1, 2011·Antioxidants & Redox Signaling·Ute JungwirthPetra Heffeter
Mar 25, 2014·Molecular Pharmaceutics·Emma E RamsayPierre J Dilda
Oct 18, 2015·Blood·Vu Minh HuaVivien M Y Chen
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Dec 10, 2009·Molecular Aspects of Medicine·Danielle Park, Pierre J Dilda
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Jan 21, 2021·Investigational New Drugs·Philip J Hogg
Sep 12, 2020·Free Radical Biology & Medicine·Alessandro CortiAlfonso Pompella

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