Characterization of the novel arsenical darinaparsin (ZIO-101, S-dimethylarsino-glutathione) as a more potent inducer of oxidative stress and apoptosis than arsenic trioxide in acute promyelocytic leukemia

Arsenic trioxide (As2O3) is an effective treatment strategy for acute promyelocytic leukemia (APL), as sensitivity to As2O3 may correlate with the induction of oxidative stress. However, the use of As2O3 in other malignancies is limited at clinically achievable doses. To expand the clinical potential of arsenic to other malignancies, a promising novel arsenical, darinaparsin (S-dimethylarsino-glutathione, ZIO-101) is more potent in vitro than As2O3 in a variety of hematopoietic malignant cell lines. At equimolar concentrations, darinaparsin is significantly more potent than As2O3 in inducing signalling pathways known to be required for arsenic-induced apoptosis. Moreover, unlike As2O 3, darinaparsin is a selective inducer of Nrf2 antioxidant responses, thereby generating unopposed oxidative stress response and apoptosis in APL. Interestingly, darinaparsin does not demonstrate sensitivity to inhibition of ABCC1 (Mrp1), a known transporter involved in resistance to arsenic, suggesting that darinaparsin may be an effective treatment in tumours that overexpress ABCC1.