Role of arsenic (+3 oxidation state) methyltransferase in arsenic mediated APL treatment: an in vitro investigation
Role of arsenic (+3 oxidation state) methyltransferase in arsenic mediated APL treatment: an in vitro investigation
复制标题
砷（3氧化态）甲基转移酶在砷介导的 APL 治疗中的作用：体外研究
DOI：
10.1039/c8mt00057c
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发表时间：
2018-06-01
期刊：
影响因子：
3.4
通讯作者：
Naranmandura, Hua
中科院分区：
文献类型：
--
作者：
Maimaitiyiming, Yasen;Wang, Chao;Naranmandura, Hua
砷(+3氧化态)甲基转移酶(AS3MT)是人体砷代谢的关键酶，它能促进三氧化二砷(As_2O_3)转化为更具活性的代谢物，如单甲基砷酸(MMA(III))和二甲基砷酸(DMA(III))。然而，目前尚不清楚AS3MT对砷的生物转化是否有助于促进急性早幼粒细胞白血病(APL)的治疗。为了了解AS3MT在APL患者中的可能作用，我们研究了亚砷酸盐(IAS(III))和三种混合砷(IAS(III)、MMA(III)和DMA(III)，以模拟血液中的活性砷物种)对NB4细胞分化和凋亡的影响。尽管混合砷对NB4细胞分化和PML-RAR融合蛋白降解的诱导作用约为IAS(III)的2倍，但其诱导细胞凋亡的能力却比IAS(III)强5倍。更重要的是，在与AS3MT基因转染的HepG2细胞共培养的Transwell系统中，IAS(III)对NB4细胞的增殖有明显的抑制作用(p<；0.05)，这表明甲基化代谢产物的产生抑制了细胞的增殖。这些结果表明，三氧化二砷(即IAS(III))对APL患者的疗效可能与AS3MT产生甲基化砷代谢产物(即MMA(III)和DMA(III))有关。
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-RAR 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.