Seminarium Instytutowe
Dr Patrycja Wińska
Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology
Anticancer properties of protein kinase CK2 inhibitors and their combinations with antimetabolites of the thymidylate biosynthesis cycle
ABSTRACT
Protein kinase CK2 has been considered as an attractive target for the development of an anti-cancer approach. Among several classes of effective CK2 inhibitors are derivatives of benzotriazole and benzimidazole e.g. 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) and 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi). We found that the introduction of a methyl group on the C2 atom of TBBi and aminoalkyl substituents on N1 led to the 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole (2-Me-TBBi) and their N-aminoalkyl derivatives with a promising anticancer and proapoptotic activity. Our results demonstrated also that N-hydroxypropyl derivatives of TBBi and 2-Me-TBBi used in the form of pro-drugs (ester forms) inhibit CK2 intracellularly more effectively than their active forms and thus show very good proapoptotic properties against breast cancer cell lines. Additionally, we demonstrated that combination of CK2 inhibitors with antimetabolites of the thymidylate biosynthesis cycle as 5-fluorouracil (5-FU) and methotrexate (MTX) decreases of cancer cell lines viability in a synergistic manner (CI<1), and makes it possible to reduce the effective dose of both antimetabolites. Our results indicate that the synergistic effect of simultaneous inhibition of CK2 and the thymidylate biosynthesis cycle in acute lymphoblastic leukaemia correlates with a decreased CK2-mediated phosphorylation of NF-κB p65 and consequently induction of apoptosis. The obtained results indicate also a correlation between the observed synergistic effect for 5-FU and CK2 inhibitors in triple negative breast cancer and activation of p38 MAPK, inhibition of FAK kinase autophosphorylation and prolongation of S-phase of cell cycle.
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