Wang Qian Qian, Zhou Xin Yi, Zhang Yan Fang, Bu Na, Zhou Jin, Cao Feng Lin, Naranmandura Hua
Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Oncotarget. 2015 Sep 22;6(28):25646-59. doi: 10.18632/oncotarget.4662.
Arsenic trioxide (As2O3) is one of the most effective therapeutic agents used for patients with acute promyelocytic leukemia (APL). The probable explanation for As2O3-induced cell differentiation is the direct targeting of PML-RARα oncoprotein by As2O3, which results in initiation of PML-RARα degradation. However, after injection, As2O3 is rapidly methylated in body to different intermediate metabolites such as trivalent monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), therefore, it remains unknown that which arsenic specie is actually responsible for the therapeutic effects against APL. Here we have shown the role of As2O3 (as iAs(III)) and its intermediate metabolites (i.e., MMA(III)/DMA(III)) in NB4 cells. Inorganic iAs(III) predominantly showed induction of cell differentiation, while MMA(III) and DMA(III) specifically showed to induce mitochondria and endoplasmic reticulum-mediated apoptosis, respectively. On the other hand, in contrast to iAs(III), MMA(III) showed stronger binding affinity for ring domain of PML recombinant protein, however, could not induce PML protein SUMOylation and ubiquitin/proteasome degradation. In summary, our results suggest that the binding of arsenicals to the ring domain of PML proteins is not associated with the degradation of PML-RARα fusion protein. Moreover, methylated arsenicals can efficiently lead to cellular apoptosis, however, they are incapable of inducing NB4 cell differentiation.
三氧化二砷（As2O3）是用于急性早幼粒细胞白血病（APL）患者的最有效治疗药物之一。As2O3诱导细胞分化的可能解释是As2O3直接靶向PML-RARα癌蛋白，从而导致PML-RARα降解的启动。然而，注射后，As2O3在体内迅速甲基化形成不同的中间代谢产物，如三价一甲基胂酸（MMA(III)）和二甲基胂酸（DMA(III)），因此，究竟哪种砷物种实际上对APL的治疗效果负责仍不清楚。在这里，我们展示了As2O3（以iAs(III)形式）及其中间代谢产物（即MMA(III)/DMA(III)）在NB4细胞中的作用。无机iAs(III)主要表现出诱导细胞分化，而MMA(III)和DMA(III)分别特异性地表现出诱导线粒体和内质网介导的凋亡。另一方面，与iAs(III)相反，MMA(III)对PML重组蛋白的环结构域显示出更强的结合亲和力，然而，不能诱导PML蛋白的SUMO化和泛素/蛋白酶体降解。总之，我们的结果表明，砷化合物与PML蛋白环结构域的结合与PML-RARα融合蛋白的降解无关。此外，甲基化的砷化合物可以有效地导致细胞凋亡，然而，它们不能诱导NB4细胞分化。
