4-(n-(s-glutathionylacetyl)amino)phenylarsenoxide and Pancreatic-Neoplasms

Plasma membrane drug efflux pumps of the multidrug resistance associated protein (MRP) family blunt the effectiveness of anticancer drugs and are often associated with drug resistance. GSAO, a tripeptide trivalent arsenical that targets a key mitochondrial transporter in angiogenic endothelial cells, is an example of a compound whose efficacy is limited by tumor cell expression of MRP isoforms 1 and 2. A cysteine mimetic analogue of GSAO was made, PENAO, which accumulates in cells 85 times faster than GSAO due to increased rate of entry and decreased rate of export via MRP1/2. The faster rate of accumulation of PENAO corresponds to a 44-fold increase in antiproliferative activity in vitro and approximately 20-fold better antitumor efficacy in vivo. This information could be used to improve the efficacy of other small molecule cancer therapeutics.

Topics: Animals; Antineoplastic Agents; Arsenicals; Biomimetics; Cattle; Cell Line, Tumor; Cell Proliferation; Cytosol; Dogs; Endothelial Cells; Extracellular Space; Female; Humans; Mice; Mitochondria; Oligopeptides; Pancreatic Neoplasms; Time Factors; Xenograft Model Antitumor Assays

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 approximately 8-fold more efficient than p-GSAO at triggering the mitochondria permeability transition in isolated mitochondria. o-GSAO was an approximately 50-fold more potent inhibitor of endothelial and tumor cell proliferation than p-GSAO. The mechanism of this effect was a consequence of approximately 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.

Topics: Angiogenesis Inhibitors; Animals; Aorta; Arsenicals; Cattle; Cell Proliferation; Endothelium, Vascular; Female; Glutathione; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Mitochondrial ADP, ATP Translocases; Multidrug Resistance-Associated Proteins; Neovascularization, Pathologic; Pancreatic Neoplasms; Stereoisomerism; Superoxides; Toluene