[In vitro study of the effects of arsenic trioxide combined with 8-CPT-cAMP on differentiation induction in retinoic acid resistant acute promyelocytic leukemia cells].
OBJECTIVE
To investigate the potential effects of arsenic trioxide (As(2)O(3)) combined with 8-(4-chlorophenylthio) adenosine 3', 5'-cyclic monophosphate (8-CPT-cAMP) on the retinoic acid (RA)-resistant acute promyelocytic leukemia (APL) cells.


METHODS
The RA resistant APL cell lines NB4-R1 and NB4-R2 were used as in vitro models. The effect of As(2)O(3) and/or 8-CPT-cAMP was evaluated according to cellular morphology, cell surface antigen and nitroblue-tetrazolium (NBT) assay. Meanwhile, immunofluorescence analysis and Western blot assay were used to detect the degradation of PML-RAR alpha fusion protein and the change of several key cell cycle regulatory proteins in these cells before and after the treatment.


RESULTS
Low dose of As(2)O(3) (0.25 micromol/L) synergized with 8-CPT-cAMP (200 micromol/L) in inducing differentiation of NB4-R1 and NB4-R2 cells, while neither of these two drugs alone could induce differentiation of these cells. In addition, 8-CPT-cAMP was able to inhibit the cell growth by modulating the expression of some important cell cycle regulators and to facilitate the As(2)O(3)-mediated degradation of PML-RAR alpha fusion protein.


CONCLUSIONS
As(2)O(3) combined with 8-CPT-cAMP could induce differentiation of RA-resistant APL cells.
Zhu
Qi
Q
Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, Shanghai 200025, China.
Yu
Yun
Y
Jia
Pei-min
PM
Cai
Xun
X
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*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D014212:Tretinoin; D000242:Cyclic AMP; D000077237:Arsenic Trioxide