Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells.
Malignant gliomas are highly resistant to current therapeutic approaches due to genetic alterations rendering them resistant to cell death. CK2, a ubiquitous and constitutively active serine/threonine kinase, frequently elevated in tumors, contributes to enhanced cell proliferation and resistance to apoptosis. Inhibition of CK2 expression or treatment with inhibitors of CK2 affected survival or induced apoptosis in various cancer cells. Here we compared cytotoxic effects of well-known and new CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), 4,5,6,7-tetrabromo-1H-benzimidazole (TBI), 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), the related 3-(4,5,6,7-tetrabromo-1H-benzimidazol-1-yl)propan-1-ol (MB001), 3-(4,5,6,7-tetrabromo-1H-1,2,3-benzotriazol-1-yl) propan-1-ol (MB002), 3-(4,5,6,7-tetrabromo-2H-1,2,3-benzotriazol-2-yl)propan-1-ol (MB003) and also structurally similar to above compounds pentabromobenzylisothiourea (ZKK1) and its derivatives (ZKK2-8) on cultured malignant glioma cells. TBI, ZKK1 and MB001-3 were more effective than TBB in inducing growth arrest and cell death in glioma cells. TBI and ZKK1 strongly induced apoptotic death involving caspase 3 and 7 activation followed by PARP cleavage. DMAT strongly upregulated the expression of cytotoxic ligand and its receptor Fas. Structural modifications of ZKK1 largely affected its efficacy: exchange of Br- to Cl- or F-substituents on the pentabromophenyl ring and inclusion of the bulky N-phenyl substituent in thiourea fragment of ZKK1 diminished cytotoxic activity, while N-substitution with short alkyl groups or an allyl group had opposite effects. Interestingly, TBI at moderate dose did not affect viability of non-transformed astrocytes, suggesting some specificity toward tumor cells in cytotoxic action. TBI, DMAT and ZKK1-induced apoptosis associated with caspase cascade activation in human malignant glioblastoma cells with mutated PT53 and PTEN genes. The reported data demonstrate that suitably modified polybromobenzene molecules exhibit a significant cytotoxic potential towards malignant glioblastoma cells.
Laboratory of Transcription Regulation, The Nencki Institute of Experimental Biology, Warsaw, Poland. bozenakk@nencki.gov.pl
Bozena
B
Kaminska
Aleksandra
A
Ellert-Miklaszewska
Agata
A
Oberbek
Pawel
P
Wisniewski
Beata
B
Kaza
Malgorzata
M
Makowska
Maria
M
Bretner
Zygmunt
Z
Kazimierczuk
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016133:Polymerase Chain Reaction; D051381:Rats
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047390:Casein Kinase II