Effect of Simultaneous Inhibition of Protein Kinase CK2 and Thymidylate Synthase in Leukemia and Breast Cancer Cells

• Published in: Anticancer research Vol. 38; no. 8; pp. 4617 - 4627
• Main Authors: Wińska, Patrycja, Skierka, Katarzyna, Łukowska-Chojnacka, Edyta, Koronkiewicz, Mirosława, Cieśla, Joanna, Bretner, Maria
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01-08-2018
• Subjects: 5-Fluorouracil; Acetonitrile; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzimidazoles; Benzimidazoles - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer; Casein kinase II; Casein Kinase II - antagonists & inhibitors; Cell Line, Tumor; Combined treatment; Female; Flow cytometry; Fluorouracil - pharmacology; Humans; Inhibition; Inhibitors; Kinases; Leukemia; Leukemia - drug therapy; Leukemia - metabolism; MCF-7 Cells; Naphthyridines - pharmacology; Protein kinase C; Protein Kinase Inhibitors - pharmacology; Proteins; Synergistic effect; Therapeutic applications; Thymidylate synthase; Thymidylate Synthase - antagonists & inhibitors; 5-fluorouracil; CX-4945; protein kinase CK2; thymidylate synthase; 4,5,6,7-tetrabromo-1H-benzimidazole; Synergism
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.12766

Protein kinase CK2 was recently identified as a promising therapeutic target for combination therapy. Our study aims to investigate the anticancer effect of a simultaneous inhibition of thymidylate synthase (TS) and CK2 in MCF-7 breast cancer and CCRF-CEM leukemia cells.
The type of interaction between CK2 inhibitors: CX-4945, 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi), or recently obtained 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazol-1-yl)acetonitrile (2b) and TS-directed anticancer drug, 5-fluorouracil (5-FU) was determined using the MTT assay and a combination index method. The influence of the combined treatment on apoptosis in leukemia cells, as well as on cell-cycle progression and the levels of TS, CK2α and P-Ser529-p65 were determined in both cell lines, using flow cytometry and western blot analysis, respectively.
The best synergistic effect was observed in CCRF-CEM cell line with the combination of 5-FU and 2b which correlated with a decrease in the endocellular CK2 activity and enhancement of the pro-apoptotic effect.
The obtained results demonstrate the ability of CK2 inhibitors to enhance the efficacy of 5-FU in anticancer treatment, indicating a different molecular mechanism of the studied CK2 inhibitors interaction with 5-FU.