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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

ZHU Qi, YU Yun, JIA Pei-min, CAI Xun, CHEN Sai-juan, CHEN Zhu, WANG Zhen-yi, TONG Jian-hua. Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, Shanghai 200025, China  
Objective To investigate the potential effects of arsenic trioxide (As 2O 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 2O 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-RARα 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 2O 3 (0.25?μmol/L) synergized with 8-CPT-cAMP (200?μmol/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 2O 3-mediated degradation of PML-RARα fusion protein. Conclusions As 2O 3 combined with 8-CPT-cAMP could induce differentiation of RA-resistant APL cells.
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