Abstract
Flavopiridol was developed as a drug for cancer therapy due to its ability to inhibit cell cycle progression by targeting cyclin-dependent kinases (CDKs). In this study, we show that flavopiridol may also have a neuroprotective action. We show that at therapeutic dosage (or at micromolar range), flavopiridol almost completely prevents colchicine-induced apoptosis in cerebellar granule neurones. In agreement with this, flavopiridol inhibits both the release of cyt c and the activation of caspase-3 induced in response to colchicine treatment. We demonstrate that in this cellular model for neurotoxicity, neither re-entry in the cell cycle nor activation of stress-activated protein kinases, such as c-Jun N-terminal kinase (JNK) or p38 MAP kinase, is involved. In contrast, we show that colchicine-induced apoptosis correlates with a substantial increase in the expression of cdk5 and Par-4, which is efficiently prevented by flavopiridol. Accordingly, a cdk5 inhibitor such as roscovitine, but not a cdk4 inhibitor such as 3-ATA, was also able to protect neurons from apoptosis as well as prevent accumulation of cdk5 and Par-4 in response to colchicine. Our data suggest a potential therapeutic use of flavopiridol in disorders of the central nervous system in which cytoskeleton alteration mediated by cdk5 activation and Par-4 expression has been demonstrated, such as Alzheimer's disease.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Animals, Newborn
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Anthracenes / pharmacology
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Anti-Bacterial Agents / pharmacology
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Apoptosis Regulatory Proteins
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Apoptosis*
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Blotting, Western
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Bromodeoxyuridine / metabolism
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CDC2-CDC28 Kinases / metabolism
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Carrier Proteins / metabolism
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Caspase 3
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Caspases / metabolism
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Cell Count
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Cell Survival
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Cells, Cultured
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Cerebellum / cytology
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Cerebellum / drug effects
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Cerebellum / physiology
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Chromatin / metabolism
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Colchicine / pharmacology*
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Cyclin E / metabolism
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 5
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Cyclin-Dependent Kinases / metabolism
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Cytochromes c / metabolism
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Flavonoids / pharmacology*
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Flow Cytometry
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Immunohistochemistry
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Intracellular Signaling Peptides and Proteins*
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JNK Mitogen-Activated Protein Kinases*
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Kainic Acid / pharmacology
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MAP Kinase Kinase 4
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Microtubules / metabolism
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Minocycline / pharmacology
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Neurons / drug effects*
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Neurons / physiology
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Neuroprotective Agents / pharmacology*
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Piperidines / pharmacology*
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Purines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Roscovitine
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Time Factors
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Tubulin / metabolism
Substances
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Amino Acid Chloromethyl Ketones
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Anthracenes
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Anti-Bacterial Agents
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Chromatin
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Cyclin E
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Flavonoids
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Intracellular Signaling Peptides and Proteins
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Neuroprotective Agents
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Piperidines
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Purines
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Tubulin
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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prostate apoptosis response-4 protein
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Roscovitine
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pyrazolanthrone
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alvocidib
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Cytochromes c
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Cyclin-Dependent Kinase 5
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CDC2-CDC28 Kinases
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Cdk2 protein, rat
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Cdk5 protein, rat
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Casp3 protein, rat
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Caspase 3
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Caspases
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Minocycline
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Bromodeoxyuridine
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Kainic Acid
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Colchicine