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.


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.


CONCLUSIONS
Combination of CK2 inhibitors and pentabromobenzylisothioureas-induced synergistic anti-leukemic effects against KG-1 acute myelogenous leukemia cells in vitro.
Department of Cell Biology, National Medicines Institute, Chełmska St. 30/34, 00-725 Warsaw, Poland. m.koronkiewicz@nil.gov.pl.
Miroslawa
M
Koronkiewicz
Zdzislaw
Z
Chilmonczyk
Zygmunt
Z
Kazimierczuk
D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013890:Thiourea / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C492322:2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D047390:Casein Kinase II; D013890:Thiourea
CK2 inhibitors; KG-1 cells; apoptosis; flow cytometry; pentabromobenzylisothioureas