Synergistic anti-leukemic effects of CK2 inhibitors and pentabromobenzylisothioureas in vitro.

Background: Casein kinase-2 (CK2) inhibitors and pentabromobenzylisothioureas are promising anti-leukemic agents for treatment, both alone and in combination. In this study, we examined pro-apoptotic and cytostatic effects of three CK2 inhibitors: one known, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) and two new: 2-(4-methylpiperazin-1-yl)-4,5,6,7-tetrabromo-1H-benzimidazole (MPT) and 2-aminoethyleneamino-4,5,6,7-tetrabromo-1H-benzimidazole (AEAT), as well as of certain S-2,3,4,5,6-pentabromobenzylisothiouronium bromides: ZKK-3, ZKK-9, ZKK-13, against the human acute myelogenous leukemia cell line (KG-1). Cells were treated with CK2 inhibitors alone and in combination with the pentabromobenzylisothioureas.

Materials And Methods: Evaluation of synergistic and pro-apoptotic effects, mitochondrial membrane potential (ΔΨm) assay, poly(ADP-ribose) polymerase (PARP) cleavage assay, and cell-cycle progression of KG-1 cells were carried out using the flow cytometric technique and fluorescent microscopic analysis. Western blots were used for analysis of B-cell lymphoma-2 (BCL-2) family proteins in whole-cell extracts.

Results: The tested CK2 inhibitors DMAT, MPT, AEAT exhibited synergistic proapoptotic effect in combination with ZKK-3, ZKK-9 and ZKK-13. The agents revealed different pro-apoptotic efficacies against leukemia cell line KG-1. The highest apoptotic activity of the tested compounds was exhibited by AEAT.

Conclusion: Combination of CK2 inhibitors and pentabromobenzylisothioureas-induced synergistic anti-leukemic effects against KG-1 acute myelogenous leukemia cells in vitro.