Role of arsenic (+3 oxidation state) methyltransferase in arsenic mediated APL treatment: an in vitro investigation

Abstract

Arsenic (+3 oxidation state) methyltransferase (AS3MT) is a key enzyme responsible for arsenic metabolism in humans, which facilitates conversion of arsenic trioxide (As₂O₃) to more reactive metabolites such as monomethylarsonous acid (MMA^III) and dimethylarsinous acid (DMA^III). However, it is unclear whether the biotransformation of arsenic by AS3MT contributes to the promotion of acute promyelocytic leukemia (APL) therapy. In order to understand the probable role of AS3MT in APL patients, we evaluated the effects of arsenite (iAs^III) and three mixed arsenicals (i.e., iAs^III, MMA^III and DMA^III, to mimic active arsenic species in the blood) on NB4 cell differentiation and apoptosis. Although the mixed arsenicals exhibited about 2 fold less effect on the induction of NB4 cell differentiation and PML-RARα fusion protein degradation, they showed 5 times stronger ability to induce apoptosis when compared with iAs^III. More importantly, the proliferation of NB4 cells was significantly (p < 0.05) inhibited in a transwell system co-cultured with AS3MT-transfected HepG2 cells after exposure to iAs^III, suggesting that the generation of methylated metabolites restrained cell proliferation. These findings indicate that the therapeutic efficacy of As₂O₃ (i.e., iAs^III) in APL patients is probably associated with the production of methylated arsenic metabolites (i.e., MMA^III and DMA^III) by AS3MT.