title: The novel arsenical darinaparsin is transported by cystine importing systems.
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.
authors.affiliation: Department of Oncology, Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Division of Experimental Medicine (N.G., G.G.J.R., M.S.D., J.N.N., S.V.d.R., K.K.M., W.H.M.), and Department of Chemistry (Y.G., D.S.B.), McGill University, Montreal, Quebec, Canada; and Cancer Research Center, Department of Biomedical Sciences, University at Albany, State University of New York, Rensselaer, New York (Y.S., D.S.C.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Garnier
authors.forename: Geneviève G J
authors.initials: GG
authors.lastname: Redstone
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dahabieh
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Nichol
authors.forename: Sonia V
authors.initials: SV
authors.lastname: del Rincon
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Gu
authors.forename: D Scott
authors.initials: DS
authors.lastname: Bohle
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Conklin
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D010087:Oxides / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; C118895:SLC7A11 protein, human; D013438:Sulfhydryl Compounds; C587955:dimethylarsino-cysteine; C515055:darinaparsin; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine; D000077237:Arsenic Trioxide