Metabolism of the tumor angiogenesis inhibitor 4-(N-(S-Glutathionylacetyl)amino)phenylarsonous acid.
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 metabolite that reacts with mitochondrial adenine nucleotide translocase. Taken together, our findings indicate that gammaGT processing of GSAO at the cell surface is the rate-limiting step in its antiangiogenic activity. This information can explain the kidney toxicity at high doses of GSAO noted in preclinical studies and will aid in the anticipation of potential side effects in humans and in the design of better antimitochondrial cancer drugs.
Dilda
Pierre J
PJ
UNSW Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
Ramsay
Emma E
EE
Corti
Alessandro
A
Pompella
Alfonso
A
Hogg
Philip J
PJ
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001152:Arsenicals / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D042783:Endothelial Cells / Q000201:enzymology*; D005978:Glutathione / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology; D027361:Organic Anion Transporters / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
C426645:4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide; D020533:Angiogenesis Inhibitors; D001152:Arsenicals; D027361:Organic Anion Transporters; D000226:Mitochondrial ADP, ATP Translocases; D005723:gamma-Glutamyltransferase; D005978:Glutathione