This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dilda, P. J. Articles by Hogg, P. J. Search for Related Content PubMed PubMed Citation Articles by Dilda, P. J. Articles by Hogg, P. J.

Para to Ortho Repositioning of the Arsenical Moiety of the Angiogenesis Inhibitor 4-(N-(S-Glutathionylacetyl)Amino)Phenylarsenoxide Results in a Markedly Increased Cellular Accumulation and Antiproliferative Activity

¹ Centre for Vascular Research, University of New South Wales; ² Department of Haematology, Prince of Wales Hospital, Sydney, Australia; and ³ Children's Cancer Institute Australia for Medical Research, Randwick, Australia

Requests for reprints: Philip J. Hogg, Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Phone: 61-2-9385-1004; Fax: 61-2-9385-1389; E-mail: p.hogg{at}unsw.edu.au.

The synthetic tripeptide arsenical 4-(N-(S-glutathionylacetyl)amino)p-phenylarsenoxide (p-GSAO) is an angiogenesis inhibitor that inactivates mitochondrial adenine nucleotide translocase (ANT) by cross-linking a pair of matrix-facing cysteine residues. This causes an increase in superoxide levels and proliferation arrest of endothelial cells followed by mitochondrial depolarization and apoptosis. p-GSAO induces proliferation arrest in endothelial cells and is a selective inhibitor of endothelial cells compared with tumor cells. An analogue of p-GSAO has been made in which the arsenical moiety is at the ortho instead of the para position on the phenyl ring. o-GSAO, like p-GSAO, bound to ANT in a dithiol-dependent manner but was 8-fold more efficient than p-GSAO at triggering the mitochondria permeability transition in isolated mitochondria. o-GSAO was an 50-fold more potent inhibitor of endothelial and tumor cell proliferation than p-GSAO. The mechanism of this effect was a consequence of 300-fold faster rate of accumulation of o-GSAO in the cells, which is due, at least in part, to impaired export by the multidrug resistance–associated protein 1. Administration of o-GSAO to tumor-bearing mice delayed tumor growth by inhibiting tumor angiogenesis but there were side effects not observed with p-GSAO administration. (Cancer Res 2005; 65(24): 11729-34)