Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells

Patrycja Wińska , Łukasz Widło , Katarzyna Skierka , Alicja Krzyśko , Mirosława Koronkiewicz , Jarosław M. Cieśla , Joanna Cieśla , Maria Bretner

Abstract

Background/Aim: Recently, we demonstrated the ability of inhibitors of protein kinase 2 (casein kinase II; CK2) to enhance the efficacy of 5-fluorouracil, a thymidylate synthase (TYMS)-directed drug for anticancer treatment. The present study aimed to investigate the antileukemic effect of simultaneous inhibition of dihydrofolate reductase (DHFR), another enzyme involved in the thymidylate biosynthesis cycle, and CK2 in CCRF-CEM acute lymphoblastic leukemia cells. Materials and Methods: The influence of combined treatment on apoptosis and cell-cycle progression, as well as the endocellular level of DHFR protein and inhibition of CK2 were determined using flow cytometry and western blot analysis, respectively. Real-time quantitative polymerase chain reaction was used to examine the influence of silmitasertib (CX-4945), a selective inhibitor of CK2 on the expression of DHFR and TYMS genes. Results: The synergistic effect was correlated with the increase of annexin Vbinding cell fraction, caspase 3/7 activation and a significant reduce in the activity of CK2. An increase of DHFR protein level was observed in CCRF-CEM cells after CX-4945 treatment, with the mRNA level remaining relatively constant. Conclusion: The obtained results demonstrate a possibility to improve methotrexate-based anti-leukemia therapy by simultaneous inhibition of CK2. The effect of CK2 inhibition on DHFR expression suggests the important regulatory role of CK2- mediated phosphorylation of DHFR inside cells.
Author Patrycja Wińska (FC / CDSB)
Patrycja Wińska,,
- Chair of Drug and Cosmetics Biotechnology
, Łukasz Widło (FC / CDSB)
Łukasz Widło,,
- Chair of Drug and Cosmetics Biotechnology
, Katarzyna Skierka (FC / CDSB)
Katarzyna Skierka,,
- Chair of Drug and Cosmetics Biotechnology
, Alicja Krzyśko (FC / CDSB)
Alicja Krzyśko,,
- Chair of Drug and Cosmetics Biotechnology
, Mirosława Koronkiewicz
Mirosława Koronkiewicz,,
-
, Jarosław M. Cieśla
Jarosław M. Cieśla,,
-
, Joanna Cieśla (FC / CDSB)
Joanna Cieśla,,
- Chair of Drug and Cosmetics Biotechnology
, Maria Bretner (FC / CDSB)
Maria Bretner,,
- Chair of Drug and Cosmetics Biotechnology
Journal seriesAnticancer Research, ISSN 0250-7005, (A 20 pkt)
Issue year2019
Vol39
No7
Pages3531-3542
Publication size in sheets0.55
Keywords in EnglishApoptosis, synergism, protein kinase CK2, dihydrofolate reductase, methotrexate, CX-4945.
ASJC Classification1306 Cancer Research; 2730 Oncology; 2700 General Medicine
DOIDOI:10.21873/anticanres.13499
URL http://ar.iiarjournals.org/content/39/7/3531
Languageen angielski
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Score (nominal)20
ScoreMinisterial score = 20.0, 17-08-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 0.669; WoS Impact Factor: 2017 = 1.865 (2) - 2017=1.876 (5)
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