PT  - JOURNAL ARTICLE
AU  - Garnier, Nicolas
AU  - Redstone, Geneviève G. J.
AU  - Dahabieh, Michael S.
AU  - Nichol, Jessica N.
AU  - del Rincon, Sonia V.
AU  - Gu, Yuxuan
AU  - Bohle, D. Scott
AU  - Sun, Yan
AU  - Conklin, Douglas S.
AU  - Mann, Koren K.
AU  - Miller, Wilson H.
TI  - The Novel Arsenical Darinaparsin Is Transported by Cystine Importing Systems
AID  - 10.1124/mol.113.089433
DP  - 2014 Apr 01
TA  - Molecular Pharmacology
PG  - 576--585
VI  - 85
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/85/4/576.short
4100  - http://molpharm.aspetjournals.org/content/85/4/576.full
SO  - Mol Pharmacol2014 Apr 01; 85
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.