Antitumor activity of the protein kinase inhibitor 1-(β-D-2′-deoxyribofuranosyl)-4,5,6,7-tetrabromo- 1H-benzimidazole in breast cancer cell lines

Abstract

Background The protein kinases CK2 and PIM-1 are involved in cell proliferation and survival, the cell cycle, and drug resistance, and they are found overexpressed in virtually all types of human cancer, including breast cancer. In this study, we investigated the antitumor activity of a deoxynucleoside derivative, the protein kinase inhibitor compound 1-(β-D-2′-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (K164, also termed TDB), inter alia CK2 and PIM-1, on breast cancer cell lines (MDA-MB-231, MCF-7, and SK-BR-3). Methods An evaluation of the cytotoxic and proapoptotic effects, mitochondrial membrane potential (ΔΨm), and cell cycle progression was performed using an MTT assay, flow cytometry, and microscopic analysis. The Western blotting method was used to analyze the level of proteins important for the survival of breast cancer cells and proteins phosphorylated by the CK2 and PIM-1 kinases. Results The examined compound demonstrated the inhibition of cell viability in all the tested cell lines and apoptotic activity, especially in the MCF-7 and SK-BR-3 cells. Changes in the mitochondrial membrane potential (ΔΨm), cell cycle progression, and the level of the proteins studied were also observed. Conclusions The investigated CK2 and PIM-1 kinase inhibitor K164 is a promising compound that can be considered a potential agent in targeted therapy in selected types of breast cancer; therefore, further research is necessary.

Synthesis and Anticancer Activity of Novel Dual Inhibitors of Human Protein Kinases CK2 and PIM-1

“…Moreover, it was demonstrated that the inactivation of BAD by PIM-1-mediated phosphorylation of Ser112 can affect BCL-2, an apoptotic cell death suppressor, which consequently leads to cell survival [57]. A similarly increased level of phospho-BAD (Ser112) was observed in TNBC MDA-MB-231 cells after treatment with a dual CK2/PIM-1 inhibitor, 1-(β-D-2 -deoxyribofuranosyl)-4,5,6,7tetrabromo-1H-benzimidazole, named K164 (TDB) [37]. Interestingly, the same inhibitor reduced the catalytic activity of both CK2 and PIM-1 kinases, as manifested by decreased phosphorylated levels of Akt and BAD in K-562 cells, and induced apoptosis in this cell line [36].…”

“…These studies have shown that the use of dual inhibitors of CK2 and PIM-1 is beneficial for the reduction in cell proliferation and induction of apoptosis in cancer cell lines, i.e., cervical cancer (HeLa) and chronic myeloid leukemia (CML) [ 35 , 36 ]. The most recent studies demonstrated that inhibitor K164 is a promising compound that can be considered a potential active agent in targeted therapy in selected types of breast cancer [ 37 ].…”

“…In this regard, intending to potentiate a DMAT-lead structure, we obtained a series of its model analogs differing in the structural topology of aliphatic amino alcohol substituents. Given that previous studies showed that breast cancer, as well as leukemic cells, is sensitive to dual CK2/PIM-1 inhibitor treatment [ 35 , 36 , 37 ], two leukemic cell lines, i.e., CCRF-CEM and K-562, and breast cancer cells, i.e., MCF-7, were used in the present study.…”

Study on Benzimidazole: A Comprehensive Review

“…The research that has been believed to have been conducted suggests that the action may also be displayed by chemicals such as thiadiazol, tetrazole, triazines, and imidazole. 43…”