Background & objective: Low dose arsenic trioxide(As2O3) is one of the effective treatments for patients with acute promyelocytic leukemia (APL). As2O3 could induce complete remission in de novo APL patients as well as in relapsed APL patients who have been resistant to all-trans retinoic acid (ATRA). However, the underlying mechanisms of As2O3-induced remission remain obscure. Therefore, we designed this study to explore the possible mechanism of low dose As2O3 in treatment of the patients with APL.
Methods: The APL cell line NB4 and primary malignant cells isolated from APL patients were used as in vitro models. Cell differentiation was determined by cell morphology, NBT reduction test and cytometry assay of cell differentiation antigens. The change of PML-RAR alpha fusion protein was analyzed by immunofluorescence and Western blot.
Results: The 0.25 mumol/L As2O3 combined with cyclic adenosine monophosphate(cAMP) analogue, 8-(4-chlorophenylthio) adenosine 3', 5'-cyclic monophosphate (8-CPT-cAMP), had induced differentiation in NB4 cell line and primary cells. It was also found that this effect could be attenuated by H89, a specific PKA inhibitor. Moreover, 8-CPT-cAMP was able to facilitate the As2O3-mediated degradation of PML-RAR alpha.
Conclusions: The 8-CPT-cAMP could enhance As2O3-induced differentiation in APL cells.