Figure 7. Molecular Mechanisms of iAs.

^III and its Trivalent Methylated Metabolites (i.e., MMA^III and DMA^III) Induced Cell Differentiation and Apoptosis in APL Cells. Arsenic trioxide in hydrolyzed form, i.e., iAs^III may cause formation of PML-RARα protein multimers, initiate the nucleation of PML-NBs, enhanced SUMOylation/ubiquitination, resulting degradation of PML-RARα fusion protein by ubiquitin/proteasome pathway, finally promoting cell differentiation leading to clinical remission. On the other hand, MMA^III and DMA^III have shown no effect on induction of PML-RARα protein degradation and APL cell differentiation. Conversely, they have strong effect on induction of apoptosis in APL cells through mitochondria and ER-dependent pathways.