ABSTRACT
The purpose of this study was to investigate the effects of Celecoxib on the proliferation of the FLT3-ITD positive and negative acute myeloid leukemia cells and its mechanism. The proliferation inhibition effect of Celecoxib with different doses on the FLT3-ITD positive cells MV4-11 and the FLT3-ITD negative K562 cells was detected by CCK-8 method, the cell apoptosis was determined by flow cytometry, and the MEK, Mcl-1, pAKT expression was tested by Western blot. The results showed that Celecoxib inhibited the proliferation of both MV4-11 and K562 cells, but the IC50 for MV4-11 was (29.14 ± 2.4) µmol/L, which was significantly lower than that of K562 cells (39.84 ± 1.0) µmol/L (P < 0.05); The induced apoptosis rate of Celecoxib at 20-80 µmol/L on MV4-11 was not observed, but there was apparent influence on K562 at the same concentration. Western blot showed that Celecoxib down-regulated the expression of MEK and Mcl-1 but did not change the expression of pAKT obviously on MV4-11 cells, while the expression of Mcl-1 was reduced a little, but no obvious change were found in the expression of MEK and pAKT on K562 cells. It is concluded that the Celecoxib can inhibit the proliferation of FLT3-ITD positive AML cells distinctly, and the potential mechanism may be related to the inhibition of the MEK/Mcl-1 signaling pathway.
Subject(s)
Humans , Apoptosis , Celecoxib , Cell Proliferation , Cyclooxygenase 2 Inhibitors , Pharmacology , Gene Expression Regulation, Leukemic , K562 Cells , Leukemia, Myeloid, Acute , Drug Therapy , Metabolism , Pathology , MAP Kinase Kinase 1 , Genetics , Myeloid Cell Leukemia Sequence 1 Protein , Genetics , Proto-Oncogene Proteins c-akt , Genetics , Pyrazoles , Pharmacology , Signal Transduction , Sulfonamides , Pharmacology , fms-Like Tyrosine Kinase 3 , GeneticsABSTRACT
The purpose of this study was to detect the minimal residual disease (MRD) in peripheral blood of newly diagnosed patients with acute myeloid leukemia (AML) on day 8 of induction chemotherapy and analyze the correlation between day 8 MRD (D8RD) and therapeutic effectiveness. 29 adult patients (13 males and 16 females, aged 16 - 75 years, median 41 years) with AML diagnosed and treated in West China Hospital from September 2009 to June 2010 were analyzed and followed up in the study. The leukemia-associated aberrant immunophenotype (LAIP) of all the patients were detected by multiparameter flow cytometry (FCM) before therapy. The level of MRD in the peripheral blood at day 8 of induction chemotherapy was detected by FCM based on the LAIP. The overall survival curve was drawn by calculation using Kaplan-Meier method using, and the comparison between different groups was carried out by Log-rank test. The results indicated that after first course therapy, the levels of peripheral D8RD in 7 out of 29 AML cases were lower than 0.01% (negative group), and that in another 22 cases were higher than 0.01% (0.08% - 55%, positive group). The sex, age, WBC, LDH, percentage of bone marrow blasts at diagnosis in these groups were not statistically different. 6 cases achieved CR (86%) in D8RD negative group, and also 6 cases achieved CR (27%) in D8RD positive group, CR rate in D8RD negative group was higher than in D8RD positive group (86% vs 27%, P < 0.05). The median follow-up of 29 cases lasted for 15 months; the 1-year overall survival rate of D8RD negative and D8RD positive groups was 100% and 39.4%, respectively (P < 0.01). It is concluded that MRD level in peripheral blood at day 8 of induction chemotherapy is an early index to predict clinical efficacy of induction therapy in AML.