Selectivity of 4,5,6,7-tetrabromobenzimidazole as an ATP-competitive potent inhibitor of protein kinase CK2 from various sources

Zień, Piotr; Bretner, Maria; Zastąpiło, Katarzyna; Szyszka, Ryszard; Shugar, David

doi:10.1016/s0006-291x(03)00928-8

Cited by 70 publications

(54 citation statements)

References 23 publications

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“…Chemicals: The 4,5,6,7-tetrabromo-1H-benzimidazole (TBI) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBB) were obtained by excessive bromination of 1H-benzimidazole or 1H-benzotriazole as described (32,33). DMAT was synthesized according to Pagano et al (34).…”

Section: Methodsmentioning

confidence: 99%

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Kaminska¹

2009

Int J Oncol

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Abstract. 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 Clor 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.

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Section: Methodsmentioning

confidence: 99%

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Kaminska¹

2009

Int J Oncol

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“…4,5,6,7-tetrabromobenzotriazole (TBB) was synthesized as described previously [19]. Phosphatases including λ-PPase, PP1, LAR, and YOP, as well as recombinant human CK2, were purchased from New England BioLabs, Inc. (Beverly, MA).…”

Section: Chemicalsmentioning

confidence: 99%

“…One of these is DRB, which is widely employed as a CK2 inhibitor, although its selectivity has not been strictly defined. We have therefore also employed TBB, which is not only a more potent ATP-competitive CK2 inhibitor [19,22], but also, when tested against a panel of more than 30 Ser/Thr and Tyr protein kinases, exhibited very high selectivity for CK2. TBB or DRB pretreatment dramatically reduced arsenic-induced nuclear Nrf2 accumulation (Supplement 2A).…”

Section: Nrf2 Is Phosphorylated By Ck2mentioning

confidence: 99%

Molecular mechanism of human Nrf2 activation and degradation: Role of sequential phosphorylation by protein kinase CK2

Bai

Reece

et al. 2007

Free Radical Biology and Medicine

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187

128

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Nrf2 is a key transcription factor in the cellular response to oxidative stress. In this study we first identify two phosphorylated forms of endogenous human Nrf2 after chemically-induced oxidative stress and provide evidence that protein kinase CK2-mediated sequential phosphorylation plays potential role in Nrf2 activation and degradation. Human Nrf2 has a predicted molecular mass of 66 kDa. However, immunoblots showed that two bands at 98 and 118 kDa, which are identified as phosphorylated forms, are increased in response to Nrf2 inducers. In addition, human Nrf2 was found to be a substrate for CK2 which mediated two steps of phosphorylation, resulting in two forms of Nrf2 migrating with differing Mr at 98 kDa (Nrf2-98) and 118 kDa (Nrf2-118). Our results support a role in which calmodulin binding regulates CK2 activity, in that cold (25 °C) in Ca 2+ -free media (cold/Ca 2+ -free) decreased both cellular calcium levels and CK2-calmodulin binding and induced Nrf2-118 formation, the latter of which was prevented by CK2 specific inhibitors. Gel-shift assays showed that the Nrf2-118 generated under cold/Ca 2+ -free conditions does not bind to the antioxidant response element, indicating that Nrf2-98 has transcriptional activity. In contrast, Nrf2-118 is more susceptible to degradation. These results provide evidence for phosphorylation by CK2 as a critical controlling factor in Nrf2-mediated cellular antioxidant response.

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“…The phosphorylation by CK2 can affect transcription factors by changing the DNA-binding activity as it is observed for c-Jun 25 and Sp1, 26 by modulating their transcriptional activities such as for MyoD, 27 HIV-1, 22 or IRF-1, 28 and by affecting protein stability, as observed for IjBa, 29,30 PTEN 31 and connexin 45.6. 32 In this work, by using classical selective inhibitors of this kinase such as apigenin, [33][34][35][36] DRB (5,6-dichloro-1-b-D-ribofuranosylbenzimidazole) 22,37,38 and TBB (4,5,6,7-tetrabromobenzotriazole), [39][40][41] we investigated the effect of hypoxia on CK2 activity and the role that this kinase may play to regulate HIF-1 activity.…”

mentioning

confidence: 99%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1a subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1a degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/ threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the b subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the a subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2a, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxiainduced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1a protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. ' 2005 Wiley-Liss, Inc.Key words: casein kinase 2; HIF-1; neoangiogenesis HIF-1 (hypoxia-inducible factor-1) is a key regulator of cell response to reduced oxygen level. In response to hypoxic conditions, HIF-1 increases the expression of downstream target genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glycolytic enzymes (aldolase A, enolase-a) and mediates adaptation of cells to decreased oxygen level. 1 The role of HIF-1 in the regulation of tumor growth by hypoxia via the initiation of angiogenesis is certainly the best example of such an adaptive response. 2 Oncogene activation and tumor-suppressor inactivation result in deregulated cellular proliferation. However, most tumors grown larger than 1 mm 3 contain regions of low oxygen tension (hypoxia) due to an imbalance between oxygen supply and consumption. Formation of new blood vessels or ''neoangiogenesis'' is thus essential for further tumor growth. It is also important to allow tumor cell dissemination at distant sites, i.e., metastasis.Several studies using HIF-1 mutant cells have shown that HIF-1 has a profound effect on tumor biology. For example, tumors grown from HIF-1a-defective embryonic stem cells display abnormal vascularity and reduced growth rate. 3 Moreover, HIF-1 is upregulated in a broad r...

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Selectivity of 4,5,6,7-tetrabromobenzimidazole as an ATP-competitive potent inhibitor of protein kinase CK2 from various sources

Cited by 70 publications

References 23 publications

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Molecular mechanism of human Nrf2 activation and degradation: Role of sequential phosphorylation by protein kinase CK2

Role for casein kinase 2 in the regulation of HIF‐1 activity

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