TY - JOUR T1 - Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells JF - Anticancer Research JO - Anticancer Res SP - 3531 LP - 3542 DO - 10.21873/anticanres.13499 VL - 39 IS - 7 AU - PATRYCJA WIŃSKA AU - ŁUKASZ WIDŁO AU - KATARZYNA SKIERKA AU - ALICJA KRZYŚKO AU - MIROSŁAWA KORONKIEWICZ AU - JAROSŁAW M. CIEŚLA AU - JOANNA CIEŚLA AU - MARIA BRETNER Y1 - 2019/07/01 UR - http://ar.iiarjournals.org/content/39/7/3531.abstract N2 - 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 V-binding 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. ER -