Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line

Abstract

Here, we report on the organic arsenical darinaparsin (ZIO-101, S-dimethylarsino-glutathione) and its anti-myeloma activity compared with inorganic arsenic trioxide. Darinaparsin induced apoptosis in multiple myeloma cell lines in a dose-dependent manner, and the addition of N-acetylcysteine, which increases intracellular glutathione (GSH), blocked cytotoxicity of both darinaparsin and arsenic trioxide. In contrast to arsenic trioxide, intracellular GSH does not appear to be important for darinaparsin metabolism, as an inhibitor of GSH synthesis, buthionine sulfoximine, had little effect on drug activity. This discrepancy was resolved when we determined the effects of thiols on drug uptake. The addition of exogenous GSH, L-cysteine, or D-cysteine prevented darinaparsin cellular uptake and cell death but had no effect on the uptake or activity of arsenic trioxide, suggesting a difference in the transport mechanism of these two drugs. In addition, gene expression profiling revealed differences in the signaling of protective responses between darinaparsin and arsenic trioxide. Although both arsenicals induced a transient heat shock response, only arsenic trioxide treatment induced transcription of metal response genes and anti-oxidant genes related to the Nrf2-Keap1 pathway. In contrast to the protective responses, both arsenicals induced up-regulation of BH3-only proteins. Moreover, silencing of BH3-only proteins Noxa, Bim, and Bmf protected myeloma cells from darinaparsin-induced cell death. Finally, treatment of an arsenic trioxide-resistant myeloma cell line with darinaparsin resulted in dose-dependent apoptosis, indicating that cross-resistance does not necessarily develop between these two forms of arsenic in multiple myeloma cell lines. These results suggest darinaparsin may be useful as an alternative treatment in arsenic trioxide-resistant hematologic cancers.

The Novel Arsenical Darinaparsin Is Transported by Cystine Importing Systems

“…We have shown previously that Dar is significantly more potent than ATO at mediating apoptosis in various malignant cell lines, and is highly active against APL cells. Moreover, consistent with others, we have shown that Dar induces significantly more intracellular arsenic accumulation than ATO when both are given at equimolar arsenic concentrations (Manshouri et al, 2005a,b;Diaz et al, 2008;Matulis et al, 2009).…”

“…Therefore, we hypothesized that Dar might enter the cell by this mechanism. Cotreatment with Dar and extracellular thiols can reduce intracellular arsenic accumulation and subsequent cell death in a myeloma cell line (Sakurai et al, 2006;Matulis et al, 2009), supporting our hypothesis that Dar uptake utilizes GSH uptake pathways. Structural analysis of Dar suggested that a putative arsenic-containing breakdown product could be dimethylarsino-cysteine (DMAC; Fig.…”

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

“…Importantly, darinaparsin is effective in ATO-resistant leukemic cell lines that overexpress multidrug-resistant protein 1/ATP-binding cassette, subfamily C, member1 (MRP1/ABCC1; refs. 3,9). Darinaparsin showed increased antiangiogenic activity in both in vitro human umbilical vascular endothelial cell microtubule formation and in vivo Matrigel plug models (10).…”

Speciation, Metabolism, Toxicity, and Protein-binding of Different Arsenic Species in Human Cells

“…It may also be used as an alternative for ATO-resistant hematological malignancies as cross-resistance between these two drugs does not appear to develop. 91,[127][128][129] While Darinaparsin shows clinical promise, the underlying mechanisms by which it metabolizes and exerts its apoptotic effects have yet to be fully understood.…”

“…91 Arsenic trioxide and Darinaparsin are uptaken by different transport mechanisms, illicit somewhat differing protective responses, and they are metabolized by cells differently. 79,91,92 Darinaparsin was initially administered in IV (intravenous) form (no first-pass metabolism), but it is currently being evaluated as an orally administered medication. Current results show activity but as with all orally taken medications, first-pass metabolism could potentially limit its bioavailability.…”