RT Journal Article
SR Electronic
T1 The Novel Arsenical Darinaparsin Is Transported by Cystine Importing Systems
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 576
OP 585
DO 10.1124/mol.113.089433
VO 85
IS 4
A1 Nicolas Garnier
A1 Geneviève G. J. Redstone
A1 Michael S. Dahabieh
A1 Jessica N. Nichol
A1 Sonia V. del Rincon
A1 Yuxuan Gu
A1 D. Scott Bohle
A1 Yan Sun
A1 Douglas S. Conklin
A1 Koren K. Mann
A1 Wilson H. Miller, Jr.
YR 2014
UL http://molpharm.aspetjournals.org/content/85/4/576.abstract
AB Darinaparsin (Dar; ZIO-101; S-dimethylarsino-glutathione) is a promising novel organic arsenical currently undergoing clinical studies in various malignancies. Dar consists of dimethylarsenic conjugated to glutathione (GSH). Dar induces more intracellular arsenic accumulation and more cell death than the FDA-approved arsenic trioxide (ATO) in vitro, but exhibits less systemic toxicity. Here, we propose a mechanism for Dar import that might explain these characteristics. Structural analysis of Dar suggests a putative breakdown product: dimethylarsino-cysteine (DMAC). We show that DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, cell cycle arrest, and cell death. We found that inhibition of γ-glutamyl-transpeptidase (γ-GT) protects human acute promyelocytic leukemia cells (NB4) from Dar, but not from DMAC, suggesting a role for γ-GT in the processing of Dar. Overall, our data support a model where Dar, a GSH S-conjugate, is processed at the cell surface by γ-GT, leading to formation of DMAC, which is imported via xCT, xAG, or potentially other cystine/cysteine importing systems. Further, we propose that Dar induces its own import via increased xCT expression. These mechanisms may explain the enhanced toxicity of Dar toward cancer cells compared with ATO.