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 FDAapproved 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: dimethylarsinocysteine (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 g-glutamyltranspeptidase (g-GT) protects human acute promyelocytic leukemia cells (NB4) from Dar, but not from DMAC, suggesting a role for g-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 g-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.

Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis

“…Tian et al reported no significant side effect of darinaparsin on fast-cycling cell populations such as those in the BM or intestine (43). Darinaparsin is currently being tested in phase 2 clinical trials for solid tumors and hematopoietic malignancies; however, its molecular mechanism of action has not been fully elucidated (51). It has been reported that ATO antagonizes both GLI1 and GLI2 (41,42), and a very recent report also suggests that darinaparsin might reduce GLI2 protein levels in prostate tumor-initiating cells (44).…”

Glutathione S-conjugates as prodrugs to target drug-resistant tumors

“…For both drugs, extracellular γGT activity is an essential and limiting step in their activation into membrane permeable compounds (Dilda et al, 2008; Garnier et al, 2014). Indeed, it has recently been demonstrated that tumor γGT could be used for therapeutic delivery (Ramsay et al, 2014).…”

“…The newly formed cysteinylglycine S -conjugates are further processed by dipeptidases/aminopeptidases to remove the glycyl group and produce cysteine S -conjugates. These compounds then re-enter the cell via various transporters including organic anion transport polypeptides and cystine/cysteine importers (Hinchman et al, 1998; Budy et al, 2006; Dilda et al, 2008, 2009; Garnier et al, 2014). In the cytosol, N -acetyl transferases create mercapturic acid versions of the xenobiotics which are generally more polar and more water soluble than the parental compound.…”

Darinaparsin Inhibits Prostate Tumor–Initiating Cells and Du145 Xenografts and Is an Inhibitor of Hedgehog Signaling

“…Therefore, other arsenicals with antitumor activity and with less toxicity and oral availability have been sought. Darinaparsin is an organic arsenic (S-dimethylarsino-glutathione; Z-101) made by conjugating dimethylarsenic to glutathione (4,5). Screening of the NCI-60 panel of cells indicated that Ic-50 concentrations with darinaparsin ranged from 0.02 to 7.3 mmol/L.…”