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

• Published in: Anticancer research Vol. 33; no. 11; pp. 4891 - 4899
• Main Authors: Koronkiewicz, Miroslawa, Chilmonczyk, Zdzislaw, Kazimierczuk, Zygmunt
• Format: Journal Article
• Language: English
• Published: Greece 01.11.2013
• Subjects: Apoptosis - drug effects; Benzimidazoles - pharmacology; Blotting, Western; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - metabolism; Cell Cycle - drug effects; Cell Proliferation - drug effects; Flow Cytometry; Humans; In Vitro Techniques; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Membrane Potential, Mitochondrial - drug effects; Poly(ADP-ribose) Polymerases - metabolism; Protein Kinase Inhibitors - pharmacology; Thiourea - chemistry; Thiourea - pharmacology; Tumor Cells, Cultured; CK2 inhibitors; apoptosis; pentabromobenzylisothioureas; flow cytometry; KG-1 cells
• ISSN: 1791-7530

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