Abstract
Darinaparsin (ZIO-101; S-dimethylarsino-glutathione; Dar) 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 supports 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 towards cancer cells compared with ATO.
- Amino Acid
- Mass Spectroscopy
- Optical spectroscopy (fluorescence, DC, etc.)
- Regulation of gene expression
- Structure/function/mechanism
- Apoptosis
- Metals and chelators
- Oxidative stress/antioxidants
- Pharmacokinetics, metabolism and activation
- Apoptosis
- The American Society for Pharmacology and Experimental Therapeutics