Next Article in Journal
Translational Potential of MicroRNAs for Preoperative Staging and Prediction of Chemoradiotherapy Response in Rectal Cancer
Next Article in Special Issue
FOXC1 Regulation of miR-31-5p Confers Oxaliplatin Resistance by Targeting LATS2 in Colorectal Cancer
Previous Article in Journal
Protecting Tumors by Preventing Human Papilloma Virus Antigen Presentation: Insights from Emerging Bioinformatics Algorithms
Previous Article in Special Issue
Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma
Open AccessArticle

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

1
Department of Pharmacology, National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
2
Department of Hematology, Military Institute of Medicine, Szaserów 128, 04-141 Warsaw, Poland
3
Temple University School of Medicine, Sol Sherry Thrombosis Research Center and FELS Institute for Cancer Research & Molecular Biology, Philadelphia, PA 19140, USA
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(10), 1544; https://doi.org/10.3390/cancers11101544
Received: 2 August 2019 / Revised: 12 September 2019 / Accepted: 10 October 2019 / Published: 12 October 2019
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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. View Full-Text
Keywords: chronic myeloid leukemia (CML); imatinib (STI571); PAK inhibitors; PAK1/2; synergy; apoptosis chronic myeloid leukemia (CML); imatinib (STI571); PAK inhibitors; PAK1/2; synergy; apoptosis
Show Figures

Figure 1

MDPI and ACS Style

Flis, S.; Bratek, E.; Chojnacki, T.; Piskorek, M.; Skorski, T. Simultaneous Inhibition of BCR-ABL1 Tyrosine Kinase and PAK1/2 Serine/Threonine Kinase Exerts Synergistic Effect against Chronic Myeloid Leukemia Cells. Cancers 2019, 11, 1544.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop