Reversal of Multidrug-Resistance in Human Leukemia Cell Line K562/A02 by Tyrosine Kinase Inhibitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4828-4828
Author(s):  
Bao-An Chen ◽  
Xue-Yun Shan ◽  
Jian Cheng ◽  
Feng Gao ◽  
Jia-Hua Ding ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Tyrosine Kinase ◽  
Cell Line ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Expression Levels ◽  
Mdr 1

Abstract Abstract 4828 Objective This study was aimed to investigate the reversible effect of tyrosine kinase inhibitors(TKI)on Multidrug resistance cell line K562/A02. Methods The expression levels of mdr-1 mRNA and bcr-abl mRNA were assayed by RT-PCR. The protein levels of P-glycoprotein (P-gp) and P210 were detected by Western blot. The DNR accumulation of K562/A02 cells were analyzed by flow cytometry (FCM). Results Analysis of the inhibition rate showed that 0.0625μmol/L Imatinib or 5nM Nilotinib alone had no effect on the inhibition of K562/A02 cells. The fluorescence intensity of intracellular DNR of Imatinib, Nilotinib in K562/A02 cells was 7.85%, 12.02% (respectively of that in K562 cells). Imatinib or Nilotonib alone could decrease the mdr-1 mRNA and bcr-abl mRNA expression levels (Imatinib 0.65±0.02, 0.87±0.02; Nilotinib 0.48±0.04, 0.73 ±0.02) respectively, all these of which were significantly lower than the K562/A02 cells group 0.96±0.01, 1.87±0.04. The P-gp and P210 protein expression levels were also down after treated with different drugs (Imatinib 0.74±0.02, 0.68±0.01; Nilotinib 0.61±0.05, 0.60±0.01; the K562/A02 cells group 0.93±0.01, 1.25±0.03). Conclusion It is concluded that multidrug resistance (MDR) can be partially reversed by Imatinib or Nilotinib. The effect of Nilotinib was greater than Imatinib. Disclosures No relevant conflicts of interest to declare.

scholarly journals p53-Induced Autophagy Regulates Chemotherapy and Radiotherapy Resistance in Multidrug Resistance Cancer Cells

Dose-Response ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 155932582110480
Author(s):  
Shumei Ma ◽  
Dejuan Kong ◽  
Xinxin Fu ◽  
Lin Liu ◽  
Yi Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Cell Line ◽  
Ovarian Cancer Cell Line ◽  
Mutant Cell ◽  
Leukemia Cell ◽  
Cancer Cell Line ◽  
Leukemic Cells ◽  
Leukemia Cell Line ◽  
Human Leukemia

Background Multidrug resistance (MDR), a major problem in oncology therapy, limits the effectiveness of anticancer drugs. Although p53 functions as a tumor suppressor, the associations between p53 status, autophagy, and MDR are complicated and conditional. Method  In this report, p53-null human ovarian cancer cell line SKOV3 and its MDR phenotype SKVCR and human leukemia cell line CEM and its MDR phenotype CEM-VLB) (p53 mutant cell line) were used. Results  Compared to parental SKOV3, the mRNA and protein levels of MAPLC3-II and Beclin1 were higher in SKVCR cells. The inhibition of autophagy by 3-MA significantly sensitized SKVCR to VCR. Conversely, in drug-resistant leukemic cells CEM-VLB, the expressions of Beclin1 and MAPLC3-II were lower than CEM. CEM and CEM-VLB cells were treated with VLB .01 or 0.5 μg/mL, respectively, and the expression of p53 and autophagy up-regulated after VLB (.01 μg/mL) treatment in CEM cells. The percentage of S-phase and G2/M phase cells up-regulated significantly by .01 μg/mL VLB in CEM, which may relate to the status of p53 of CEM cells. A combination of radiation with 3-MA significantly increased apoptosis in CEM-VLB cells. Conclusion  Our discovery found that p53 is an important regulator controlling the balance between autophagy and MDR, as a potential drug target for ovarian cancer and leukemia.

Expression of miR-188 and 362 Induced by Erythropoietin Stimulation in a Human Erythrocytic Leukemia Cell Line.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2210-2210
Author(s):  
Keiichi Sugiura ◽  
Nobuyoshi Kosaka ◽  
Yusuke Yamamoto ◽  
Yusuke Yoshioka ◽  
Hiroshi Miyazaki ◽  
...  
Keyword(s):  
Cell Line ◽  
Real Time ◽  
Real Time Pcr ◽  
Molecular Mechanisms ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Transcriptional Level ◽  
Human Leukemia ◽  
Dependent Manner ◽  
Expression Levels

Abstract MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level and participate in a lot of biological processes. Several studies indicated that miRNAs play an important role in hematopoietic system. It has not been elucidated well about miRNAs involved in cytokine-regulated molecular mechanisms in cellular proliferation and differentiation. We screened specific miRNAs expressed in human leukemia cell lines, UT-7 and its sublines UT-7/GM, UT-7/EPO and UT-7/TPO, which exhibit hematopoietic lineage properties depending on cytokine stimuli by GM-CSF, erythropoietin (EPO), or thrombopoietin (TPO), respectively. The expression profiles of 470 miRNAs in all were analyzed using LNA-based microarray between UT-7/GM, UT-7/EPO and UT-7/TPO cells. The initial microarray data were validated, and specific expressions of several miRNAs were confirmed using quantitative real-time PCR. Especially, the expression levels of miR-188 and 362 clustered on X chromosome were significantly higher in UT-7/EPO cells as compared with those in UT-7, UT-7/GM and UT-7/TPO cells. To assess the effect of EPO on the expression of miR-188 and 362, UT-7/EPO cells were cultured under various concentration of EPO (0 to 10 U/ml) after cytokine withdrawal for 24 hours. Quantification of miRNAs expression by real-time PCR showed that miR-188 and 362 were increased 2- to 20-fold by EPO stimuli, but both expressions were not in dose-dependent manner. Furthermore, the addition of EPO (1 ng/ml) to growth factor-derived UT-7 cells which were cultured for 1 month caused a 4- to 50-fold increase of miR-362 expression; while miR-188 expression was not increased. Similarly, EPO induced the expression of miR-362 in erythroleukemic cell line TF-1. The expression levels of miR-188 and miR-362 were significantly higher in UT-7/EPO with erythrocytic features than UT-7/GM and UT-7/TPO cells, in addition, expressions of both miRNAs were induced by EPO stimuli in UT-7/EPO cells, suggesting that miR-188 and miR-362 are involved in lineage specific molecular mechanisms of erythropoiesis.

A new apoptosis inhibitor, CIAPIN1 (cytokine-induced apoptosis inhibitor 1), mediates multidrug resistance in leukemia cells by regulating MDR-1, Bcl-2, and Bax

2007 ◽  
Vol 85 (6) ◽  
pp. 741-750 ◽  
Author(s):  
Xiaohua Li ◽  
Liu Hong ◽  
Yunping Zhao ◽  
Haifeng Jin ◽  
Rui Fan ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cell Line ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Leukemia Cells ◽  
Luciferase Reporter ◽  
Chemotherapeutic Drugs ◽  
Induced Apoptosis ◽  
Apoptosis Inhibitor ◽  
Mdr 1

We investigated the role of cytokine-induced apoptosis inhibitor 1 (CIAPIN1), a newly identified apoptosis inhibitor, in leukemia cell multidrug resistance (MDR) and its possible underlying mechanisms. CIAPIN1 was found to be overexpressed at the mRNA and protein levels in the vincristine-induced multidrug-resistant leukemia cell line HL-60/VCR, compared with HL-60, its parental cell line. In this study, we transfected HL-60 with a eukaryotic expression vector of CIAPIN1. In vitro drug sensitivity assays suggested that HL-60-CIAPIN1 cells conferred resistance to both P-glycoprotein (P-gp)-related and -unrelated drugs. Blocking CIAPIN1 expression in HL-60/VCR cells by CIAPIN1-specific small interfering RNA increased the cells' sensitivity to various chemotherapeutic drugs. Flow cytometry results suggested that CIAPIN1 expression could suppress adriamycin-induced apoptosis, accompanied by a decreased accumulation and increased release of adriamycin. Semiquantitative RT–PCR, Western blot analysis, and luciferase reporter assays suggested that CIAPIN1 could significantly upregulate the expression of MDR-1 and Bcl-2, the transcription of the MDR-1 gene, as well as downregulate the expression of Bax. Additionally, the inhibition of CIAPIN1 expression by RNA interference or P-gp inhibitor could partially reverse CIAPIN1-mediated MDR. Taken together, our findings suggest that downregulating CIAPIN1 could sensitize leukemia cells to chemotherapeutic drugs by downregulating MDR-1 and Bcl-2 and by upregulating Bax, yet not altering either glutathione-S-transferase activity or intracellular glutathione content in leukemia cells. Further study of CIAPIN1's function may reveal more of the mechanisms of leukemia MDR and result in the development of strategies to treat leukemia.

Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 925-932 ◽  
Author(s):  
Michael C. Heinrich ◽  
Diana J. Griffith ◽  
Brian J. Druker ◽  
Cecily L. Wait ◽  
Kristen A. Ott ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Map Kinase ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Tyrosine Kinase Activity ◽  
Sti 571

Abstract STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.

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