264 POSTER A novel arsenical, darinaparsin, induces apoptosis in arsenic trioxide-resistant and MRP1/ABCC1-overexpressing cell lines

Mann, K.; Diaz, Zuanel; Marcoux, Simon; Kourelis, Maria; Colombo, Myrian; Komarnitsky, Philip; Abbadessa, Giovanni; Miller, William H.

doi:10.1016/s1359-6349(08)72198-0

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“…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).…”

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confidence: 99%

“…Further, darinaparsin induces higher reactive oxygen species levels than those induced by ATO. Both darinaparsin and ATO-induced cytotoxicity are c-Jun-NH 2 -kinase dependent, but only ATO-induced cytotoxicity is dependent on apoptosis signal-regulating kinase 1 (7). 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).…”

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

Tsimberidou

Camacho

Verstovšek³

et al. 2009

Clinical Cancer Research

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Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for z4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. Conclusions: The recommended dose for phase II trials is 300 mg/m 2 i.v. given daily for 5 days every 4 weeks.Arsenic has been used medicinally for >2,400 years (1).Arsenic trioxide (ATO), an inorganic arsenic compound, is approved for the treatment of relapsed acute promyelocytic leukemia. However, the use of ATO is limited by its narrow range of activity and systemic toxicity, most notably cardiotoxicity and neurotoxicity (2 -4). S-dimethylarsino-glutathione (ZIO-101; darinaparsin), a small-molecule organic arsenic compound, was synthesized by conjugating dimethylarsenic acid to glutathione. Darinaparsin was selected for development by The University of Texas M. D. Anderson Cancer Center and Texas A&M University from a number of organic arsenic derivatives because of its in vitro and in vivo antitumor activity (5, 6).Darinaparsin and ATO inhibit the growth of malignant cells in vitro by inducing cell cycle arrest and apoptosis. The mechanism of action of darinaparsin involves induction of mitochondrial damage, which, in turn, results in ATP depletion and apoptosis. 5 In vitro data showed that, in contrast to ATO, darinaparsin does not modulate bcl-2 and its mechanism of apoptosis induction is independent from promyelocytic leukemia/retinoic acid receptor a and/or promyelocytic leukemia proteins. In addition, the cytotoxicity of darinaparsin, unlike that of ATO, is unaffected by modulation of glutathione levels. Further, darinaparsin induces higher reactive oxygen species levels than those induced by ATO. Both darinaparsin and ATO-induced cytotoxicity are c-Jun-NH 2 -kinase dependent, but only ATO-induced cytotoxicity is dependent on apoptosis signal-regulating kinase 1 (7). 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 5 A. Heyfets, E. Flescher. A new organic arsenic derivate, darinaparsin, acts directly on isolated human cancer cell mitochondria, submitted manuscript.

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