scholarly journals Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model

Haematologica ◽  
2019 ◽  
Vol 105 (5) ◽  
pp. 1274-1284 ◽  
Author(s):  
Bing Z. Carter ◽  
Po Yee Mak ◽  
Hong Mu ◽  
Xiangmeng Wang ◽  
Wenjing Tao ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Murine Model ◽  
Myeloid Leukemia

scholarly journals Simultaneous Inhibition of BCR-ABL1 Tyrosine Kinase and PAK1/2 Serine/Threonine Kinase Exerts Synergistic Effect against Chronic Myeloid Leukemia Cells

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1544 ◽  
Author(s):  
Sylwia Flis ◽  
Ewelina Bratek ◽  
Tomasz Chojnacki ◽  
Marlena Piskorek ◽  
Tomasz Skorski
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Synergistic Effect ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemia Cells ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Simultaneous Inhibition

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in the chronic phase (CML-CP). However, it is unlikely that they can completely “cure” the disease. This might be because some subpopulations of CML-CP cells such as stem and progenitor cells are resistant to chemotherapy, even to the new generation of TKIs. Therefore, it is important to look for new methods of treatment to improve therapeutic outcomes. Previously, we have shown that class I p21-activated serine/threonine kinases (PAKs) remained active in TKI-naive and TKI-treated CML-CP leukemia stem and early progenitor cells. In this study, we aimed to determine if simultaneous inhibition of BCR-ABL1 oncogenic tyrosine kinase and PAK1/2 serine/threonine kinase exert better anti-CML effect than that of individual treatments. PAK1 was inhibited by small-molecule inhibitor IPA-3 (p21-activated kinase inhibitor III), PAK2 was downregulated by specific short hairpin RNA (shRNA), and BCR-ABL1 tyrosine kinase was inhibited by imatinib (IM). The studies were conducted by using (i) primary CML-CP stem/early progenitor cells and normal hematopoietic counterparts isolated from the bone marrow of newly diagnosed patients with CML-CP and from healthy donors, respectively, (ii) CML-blast phase cell lines (K562 and KCL-22), and (iii) from BCR-ABL1-transformed 32Dcl3 cell line. Herein, we show that inhibition of the activity of PAK1 and/or PAK2 enhanced the effect of IM against CML cells without affecting the normal cells. We observed that the combined use of IM with IPA-3 increased the inhibition of growth and apoptosis of leukemia cells. To evaluate the type of interaction between the two drugs, we performed median effect analysis. According to our results, the type and strength of drug interaction depend on the concentration of the drugs tested. Generally, combination of IM with IPA-3 at the 50% of the cell kill level (EC50) generated synergistic effect. Based on our results, we hypothesize that IM, a BCR-ABL1 tyrosine kinase inhibitor, combined with a PAK1/2 inhibitor facilitates eradication of CML-CP cells.

Combined Targeting of Bcl-2 and Bcr-Abl Tyrosine Kinase Eradicates Chronic Myeloid Leukemia Stem/Progenitor Cells

2015 ◽  
Vol 15 ◽  
pp. S34 ◽  
Author(s):  
Bing Z. Carter ◽  
Po Yee Mak ◽  
Hong Mu ◽  
Hongsheng Zhou ◽  
Duncan H. Mak ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Abl Tyrosine Kinase

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2843-2853 ◽  
Author(s):  
Mhairi Copland ◽  
Francesca Pellicano ◽  
Linda Richmond ◽  
Elaine K. Allan ◽  
Ashley Hamilton ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Hematopoietic Stem

Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with less than 1% recovery of Philadelphia-positive long-term culture-initiating cells. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a tyrosine kinase inhibitor and equally effective in cell lines harboring wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML.

scholarly journals Сharacteristics of proliferation and differentiation of erythroid progenitor cells at chronic myeloid Leukemia in cells culture in vivo

2016 ◽  
Vol 20 (1) ◽  
pp. 65-68
Author(s):  
I. Sviezhentseva ◽  
D. Bilko ◽  
N. Bilko ◽  
I. Dyagil
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Leukemic Cells ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Proliferation And Differentiation

The article presents a study of proliferation and differentiation features of erythroid progenitor cells of patients with chronic myeloid leukemia during the treatment with tyrosine kinase inhibitors – imatinib and nilotinib. The cultivation results showed an increase in proliferative activity of erythropoiesis progenitor cells both in the case of patients with leukemia, diagnosed for the first time, and in the case of bone marrow samples of patients with a resistance of leukemic cells clone to treatment with tyrosine kinase inhibitors. Moreover, the results showed an inhibition of erythroid progenitor cell differentiation and acquisition of resistance to tyrosine kinase inhibitors by leukemic cells clone.

scholarly journals Simultaneous Inhibition of BCR-ABL1 Tyrosine Kinase and PAK1/2 Serine/Threonine Kinases Exerts Synergistic Effect Against Chronic Myeloid Leukemia Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4143-4143
Author(s):  
Sylwia Flis ◽  
Ewelina Bratek ◽  
Tomasz Chojnacki ◽  
Marlena Piskorek ◽  
Tomasz Skorski
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Synergistic Effect ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Phase Cell ◽  
Advanced Therapies ◽  
Simultaneous Inhibition ◽  
Threonine Kinases

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of BCR-ABL1 tyrosine kinase - positive chronic myeloid leukemia in chronic phase (CML-CP). However, it is unlikely that TKIs will "cure" the disease in majority of patients because CML-CP cells are elusive targets even for the most advanced therapies employing second and third generation of TKIs. Therefore, new treatment modalities are necessary to improve therapeutic outcomes. We showed before that class I p21-activated serine/threonine kinases (PAKs) remained active in TKI-naive and TKI-treated CML-CP leukemia stem and early progenitor cells. The aim of the study was to test whether simultaneous inhibition of signaling pathways activated by BCR-ABL1 and PAK kinases may improve the treatment of CML. Special attention was focused on PAK1 and PAK2, which are expressed in hematopoietic cells and can play an important role in the promotion of CML cells proliferation and survival. PAK kinases were targeted by small molecule inhibitor IPA-3 (inhibitor of PAK1) and shRNA construct for PAK2, BCR-ABL1 kinase was inhibited by imatinib. The studies were carried out using (i) primary CML-CP stem/early progenitor cells and normal hematopoietic counterparts isolated from the bone marrow of newly diagnosed CML-CP patients and healthy donors, respectively, (ii) CML-blast phase cell lines (K562 and KCL-22), and (iii) BCR-ABL1-transformed 32Dcl3 cell line cells. We show here that inhibition of PAK1 or/and PAK2 kinases activity enhanced the effect of IM against CML cells without affecting normal counterparts. We observed that the combined use of IM with IPA-3 increased growth inhibition and apoptosis of leukemia cells. To evaluate the type of drugs interaction median effect analysis method was used. The studies revealed that the type and strength of drug interaction depend on drug concentration. Generally, combination of IM with IPA-3 at the 50% of the cell kill level (EC50) generated synergistic effect. Altogether, we postulate that BCR-ABL1 kinase inhibitor should be combined with PAK1/2 inhibitor to facilitate eradication of CML cells. Disclosures No relevant conflicts of interest to declare.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

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