Phenylarsine Oxide Can Induce the Arsenite-Resistance Mutant PML Protein Solubility Changes

Abstract

Arsenic trioxide (As2O3) has recently become one of the most effective drugs for treatment of patient with acute promyelocytic leukemia (APL), and its molecular mechanism has also been largely investigated. However, it has been reported that As2O3 resistant patients are frequently found in relapsed APL after consolidation therapy, which is due to the point mutations in B-box type 2 motifs of promyelocytic leukemia (PML) gene. In the present study, we for the first time establish whether organic arsenic species phenylarsine oxide (PAO) could induce the mutant PML-IV (A216V) protein solubility changes and degradation. Here, three different PML protein variants (i.e., PML-IV, PML-V and mutant PML-A216V) were overexpressed in HEK293T cells and then exposed to PAO in time- and dose-dependent manners. Interestingly, PAO is found to have potential effect on induction of mutant PML-IV (A216V) protein solubility changes and degradation, but no appreciable effects were found following exposure to high concentrations of iAsIII, dimethylarsinous acid (DMAIII) and adriamycin (doxorubicin), even though they cause cell death. Our current data strongly indicate that PAO has good effects on the mutant PML protein solubility changes, and it may be helpful for improving the therapeutic strategies for arsenic-resistant APL treatments in the near future.

Phenylarsine Oxide Can Induce Degradation of PLZF-RARα Variant Fusion Protein of Acute Promyelocytic Leukemia

“…Phenylarsine oxide (PAO) is one of the organic arsenic derivatives and is a potential compound to treat ATO resistant APL as well as other various refractory solid tumors . In our previous study, we found that PAO successfully induced the degradation of arsenic trioxide resistant mutated PML-RARα fusion protein . It was also used for apoptosis induction in arsenic resistant NB4 cell lines .…”

“…In fact, fusion protein solubility changes (i.e., soluble fraction of protein is shifting to insoluble fraction) by arsenic are considered as a key step for fusion protein degradation . When PLZF-RARα overexpressed Hela cells were exposed to PAO at different concentrations (1 μM to 3 μM) for 6 h, it was found that 3 μM PAO could induce PLZF-RARα fusion protein solubility changes following degradation.…”

“…It is postulated that apoptotic pathway initiation is responsible for the solubility change and degradation of fusion protein. It was already reported that toxic arsenic compounds dimethylarsinous acid (DMA III ) and adriamycin (e.g., ADR, a chemotherapeutic anticancer agent) could induce apoptosis and cell death but were ineffective to promote solubility changes and degradation of ATO-resistant mutant PML and PML-RARα fusion proteins different from PAO . Because PAO is protein tyrosine kinase inhibitor and it also has high binding affinity, stability, and permeability, these effects of PAO are quite different from the DMA III .…”