Kinetics of inhibition by 5,6-dichloro-1-<i>β</i>-<scp>d</scp>-ribofuranosylbenzimidazole on calf thymus casein kinase II

Zandomeni, Rubén

doi:10.1042/bj2620469

Cited by 54 publications

(49 citation statements)

References 26 publications

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“…DRB, a classic inhibitor of transcription, principally inhibits CDK9, the kinase component of positive transcription elongation factor b, and blocks global RNA polymerase II -dependent transcription (22,23). Additionally, DRB also inhibits other protein kinases involved in cellular metabolism such as casein kinase type II (24,25).…”

Section: Introductionmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination

Cheok

Dey

Lane

2007

Molecular Cancer Research

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Current chemotherapy focuses on the use of genotoxic drugs that may induce general DNA damage in cancer cells but also high levels of toxicity in normal tissues. Nongenotoxic activation of p53 by targeting specific molecular pathways therefore provides an attractive therapeutic strategy in cancers with wild-type p53. Here, we explored the antitumor potential of cyclin-dependent kinase (CDK) inhibitors in combination with a small molecule inhibitor of p53-murine double minute 2 (MDM2) interaction. We show that low doses of CDK inhibitors roscovitine and DRB synergize with the MDM2 antagonist nutlin-3a in the induction of p53 activity and promote p53-dependent apoptosis in a dose-and timedependent manner. Statistical measurement of the combination effects shows that the drug combination is additive on the reduction of cell viability and synergistic on inducing apoptosis, a critical end point of cytotoxic drugs. The degree of apoptosis observed 24 to 48 h after drug treatment correlated with the accumulation of p53 protein and concomitant induction of proapoptotic proteins Puma and PIG3. The antiproliferative and cytotoxic effects of this drug combination are validated in a range of tumor-derived cells including melanoma, colon carcinoma, breast adenocarcinoma, and hepatocarcinoma cells. Furthermore, this drug combination does not induce phosphorylation of Ser 15 on p53 and does not induce genotoxic stress in the cell. Given that many cytotoxic drugs rely on their ability to induce apoptosis via DNA damage -mediated activation of p53, the data presented here may provide a new therapeutic approach for the use of CDK inhibitors and MDM2 antagonists in combinatorial drug therapy.

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Section: Introductionmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination

Cheok

Dey

Lane

2007

Molecular Cancer Research

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“…Neither could we show co-precipitation of CK II with ACE (data not shown). The CK II inhibitor DRB [38], however, lead to a small increase in the amount of ACE ectodomain in the medium of one cell preparation. CK II phosphorylation of ACE (Ser 1270 ) may therefore be involved in preadipocyte ACE shedding if these preliminary data were to be confirmed.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme signalling in human preadipocytes and adipocytes

2006

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Abstract:Angiotensin-converting enzyme (ACE, kininase II) is a plasma membrane zinc metallopeptidase that acts as a key enzyme for the extracellular conversion of vasoactive peptides. Recently, ACE outside-in signalling in endothelial cells has been described. The present study tested the hypothesis that ACE signalling is not restricted to endothelial cells and may act as an additional peptide receptor on human preadipocytes and adipocytes. ACE protein levels were not changed during adipose conversion of human primary preadipocytes. The enzyme was primarily localized to the nondetergent-resistant fraction of the membrane and phosphorylated in non-dividing cells. Antibody arrays of whole cell lysate detected putative ACE-interacting proteins, which all share important roles in cell cycle control and/or apoptosis. These findings suggest that ACE is a versatile molecule, involved both in the regulation of extracellular peptide concentrations and direct intracellular signalling. In human adipose cells ACE may potentially influence exit from the cell cycle, differentiation, and programmed cell death signalling.

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“…Among these are multiple kinase inhibitors, such as sorafenib and gefitinib (Johnstone et al, 2008). Unlike DRB and some of its derivatives, many of these inhibitors have been shown to be of rather modest target selectivity (Karaman et al, 2008;Meggio et al, 1990;Zandomeni and Weinmann, 1984). It is therefore conceivable that synergies observed in TRAIL co-treatments could in part be mediated by impaired CK2 activity or Bid phosphorylation.…”

Section: The Lag Time Between Caspase-8 and Bid Activation Is Sensitimentioning

confidence: 99%

“…To achieve rapid and specific CK2 inhibition in all cells observed, we employed a short (2 hour) pretreatment with the specific CK2 inhibitor 5,6-dichloro-l-(-D-ribofuranosyl-1)-benzimidazole (DRB) (Meggio et al, 1990;Zandomeni and Weinmann, 1984). Time-lapse imaging of control HeLa cells, as expected, showed that the IETD FRET probe was cleaved before tBid-Cherry translocation could be detected (Fig.…”

Section: The Lag Time Between Caspase-8 and Bid Activation Is Sensitimentioning

confidence: 99%

Activity of protein kinase CK2 uncouples Bid cleavage from caspase-8 activation

Hellwig

Ludwig-Gałęzowska

Concannon

et al. 2010

Journal of Cell Science

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SummaryIn the present study, we quantitatively analysed the interface between apoptosis initiation and execution by determining caspase-8 activation, Bid cleavage and mitochondrial engagement (onset of mitochondrial depolarisation) in individual HeLa cervical cancer cells following exposure to tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Employing resonance-energy-transfer probes containing either the caspase-8 recognition site IETD or full-length Bid, we observed a significant delay between the times of caspase-8 activation and Bid cleavage, suggesting the existence of control steps separating these two processes. Subsequent analyses suggested that the divergence of caspase-8 activation and Bid cleavage are critically controlled by kinase signalling: inhibiting protein kinase CK2 by using 5,6-dichloro-l-(-D-ribofuranosyl-1)-benzimidazole (DRB) or by overexpression of a dominant-negative CK2 catalytic subunit largely eliminated the lag time between caspase-8 activation and Bid cleavage. We conclude that caspase-8 activation and Bid cleavage are temporally uncoupled events, providing transient tolerance to caspase-8 activities.

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Kinetics of inhibition by 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole on calf thymus casein kinase II

Cited by 54 publications

References 26 publications

Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination

Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination

Angiotensin-converting enzyme signalling in human preadipocytes and adipocytes

Activity of protein kinase CK2 uncouples Bid cleavage from caspase-8 activation

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