The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia

Abstract

Chemoresistance and high incidence of relapse in acute myeloid leukemia (AML) patients are associated with thioredoxin (Trx) overexpression. Thus, targeting the Trx system has emerged as a promising approach to treating AML. Both arsenicals and azelaic acid (AZA) are thioredoxin reductase (TrxR) inhibitors and possess antileukemic effects. In this study, to exploit agents with higher potency and lower toxicity, we got some organic arsenicals and further synthesized a series of targeted compounds by binding AZA to organic arsenicals, and then screened the most effective one, N-(4-(1, 3, 2-dithiarsinan-2-yl) phenyl)-azelamide (A-Z2). A-Z2 showed a stronger inhibitory effect against TrxR activity and in AML cell lines than did AZA or arsenicals. Additionally, A-Z2 was less toxic to healthy cells compared with traditional chemotherapeutic drugs. A-Z2 induces apoptosis by collapsing of mitochondrial membrane potential, reducing ATP level, releasing of cytochrome c and TNF-α, activating of caspase 9, 8 and 3. Analysis of the mechanism revealed that A-Z2 activates the intrinsic apoptotic pathway by directly selectively targeting TrxR/Trx and indirectly inhibiting NF-κB. A-Z2's better efficacy and safety profile against arsenicals and azelaic acid were also evident in vivo. A-Z2 had better plasma stability and biological activity in rats. A-Z2-treated mice displayed significant symptom relief and prolonged survival in a patient-derived xenograft (PDX) AML model. Herein, our study provides a novel antitumor candidate and approach for treating AML.

Keywords: Acute myeloid leukemia; NF-κB; Organic arsenicals; Thioredoxin reductase; TrxR inhibitor.