[Experimental study of low dose arsenic trioxide in treatment of patients with acute promyelocytic leukemia].
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.
Jia
Pei-min
PM
Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, P. R. China.
Zhu
Qi
Q
Yu
Yun
Y
Chen
Guo-qiang
GQ
Chen
Sai-juan
SJ
Chen
Zhu
Z
Wang
Zhen-yi
ZY
Tong
Jian-hua
JH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D013449:Sulfonamides; D013873:Thionucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010087:Oxides; D013449:Sulfonamides; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000077237:Arsenic Trioxide