The novel arsenical darinaparsin is transported by cystine importing systems

Mol Pharmacol. 2014 Apr;85(4):576-85. doi: 10.1124/mol.113.089433. Epub 2014 Jan 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / metabolism
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology
  • Arsenic Trioxide
  • Arsenicals / metabolism*
  • Arsenicals / pharmacology
  • Biological Transport
  • Cell Line, Tumor
  • Cysteine / analogs & derivatives
  • Cysteine / metabolism
  • Glutathione / analogs & derivatives*
  • Glutathione / metabolism
  • Glutathione / pharmacology
  • Humans
  • Oxides / pharmacology
  • Sulfhydryl Compounds / metabolism
  • gamma-Glutamyltransferase / metabolism

Substances

  • Amino Acid Transport System y+
  • Antineoplastic Agents
  • Arsenicals
  • Oxides
  • SLC7A11 protein, human
  • Sulfhydryl Compounds
  • dimethylarsino-cysteine
  • darinaparsin
  • gamma-Glutamyltransferase
  • Glutathione
  • Cysteine
  • Arsenic Trioxide