A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines

Abstract

Inorganic arsenic trioxide (As 2 O 3 ) is a highly effective treatment for acute promyelocytic leukemia (APL). However, other cancers do not respond well to this form of arsenic at clinically achievable doses. We tested a novel arsenical, S-dimethylarsino-glutathione (darinaparsin) for efficacy in various malignancies in vitro. Darinaparsin is significantly more potent than As 2 O 3 at mediating apoptosis in various malignant cell lines and is highly active against APL cells derived for As 2 O 3 resistance. We provide evidence that darinaparsin triggers apoptosis by inducing signaling pathways that do not completely overlap with As 2 O 3 . We show that darinaparsin induces apoptosis and oxidative stress to a greater extent than As 2 O 3 , although like As 2 O 3 , darinaparsin-induced toxicity is c-Jun NH 2 -terminal kinase-dependent. However, darinaparsin does not induce promyelocytic leukemia/retinoic acid receptor a (PML/ RARa) degradation or rearrange PML nuclear bodies in APL cells, nor is its toxicity increased by glutathione depletion. Darinaparsin treatment results in higher intracellular arsenic accumulation when compared to As 2 O 3 treatment. This may be explained by our finding that As 2 O 3 , but not darinaparsin, is efficiently exported by ABCC1, suggesting increased therapeutic efficacy of darinaparsin in ABCC1-overexpressing tumors. Our studies indicate that darinaparsin efficiently kills tumor cells with increased antioxidant capacity and drug exporters and suggest that darinaparsin may have a broader therapeutic spectrum than As 2 O 3 .

A Phase I Clinical Trial of Darinaparsin in Patients with Refractory Solid Tumors

“…In addition, darinaparsin exerts antitumor activity against ATO-resistant cell lines overexpressing multidrug resistance protein 1/ATP-binding cassette, subfamily C, member 1 (MRP1/ABCC1). Unlike ATO, darinaparsin does not seem to be the substrate of the MRP1/ABCC1 efflux pump because MRP1/ABCC1 inhibition has no effect on intracellular arsenic levels in cells exposed to darinaparsin (8). These data suggest that darinaparsin may be more effective than ATO, particularly in tumors having increased MRP1/ABCC1 efflux pump expression as a means of resistance.…”

“…Patients with acute arsenic poisoning typically present with gastrointestinal symptoms that include nausea, vomiting, abdominal pain, and diarrhea, followed by dehydration, hypotension, cardiac instability, and, more rarely, shock and death (35 -37). 7,8 Dimercaprol, hemodialysis, and 2,3-dimercapto-1-propanesulfonate have been used to treat arsenic poisoning, with variable results (38,39). The majority of adverse events related to arsenic are attributed to inactivated enzymes in the cellular energy pathway, whereby arsenic reacts with the thiol groups of proteins and enzymes, thus inhibiting their catalytic activity (40 -42).…”

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

“…Collectively, these results suggest that GLI2 is a novel therapeutic target in kidney fibrosis; however, darinaparsin is an arsenical with an uncertain long-term safety profile, even though it has reduced toxicity when compared with ATO (43,50). This could complicate efforts to develop darinaparsin as an antifibrotic treatment for patients with CKD.…”

Selenium uptake through cystine transporter mediated by glutathione conjugation

“…Cancer cells were reported to increase GSH synthesis to balance their increased oxidative stress (Chandel et al, 2000;Narang et al, 2003;Huang et al, 2005). In addition, xCT expression, in most cases, has been associated with tumor growth and drug resistance (Banjac et al, 2008;Diaz et al, 2008;Jamali et al, 2015). In this manner, SDG would be expected to exert cytotoxicity selectively against cancer cells, especially those that are highly malignant.…”