Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis.

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.
Authors	Elvira G Jorda, Ester Verdaguer, Anna M Canudas, Andrés Jiménez, Alejandra Bruna, Carme Caelles, Ramona Bravo, Elena Escubedo, David Pubill, Jordi Camarasa, Mercè Pallàs, Antoni Camins
Journal	Neuropharmacology (Neuropharmacology) Vol. 45 Issue 5 Pg. 672-83 (Oct 2003) ISSN: 0028-3908 [Print] England
PMID	12941380 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Amino Acid Chloromethyl Ketones Anthracenes Anti-Bacterial Agents Apoptosis Regulatory Proteins Carrier Proteins Chromatin Cyclin E Enzyme Inhibitors Excitatory Amino Acid Agonists Flavonoids Intracellular Signaling Peptides and Proteins Neuroprotective Agents Piperidines Purines Tubulin benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone prostate apoptosis response-4 protein Roscovitine pyrazolanthrone alvocidib Cytochromes c Cyclin-Dependent Kinase 5 CDC2-CDC28 Kinases Cdk2 protein, rat Cdk5 protein, rat Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase 4 Mitogen-Activated Protein Kinase Kinases Casp3 protein, rat Caspase 3 Caspases Minocycline Bromodeoxyuridine Kainic Acid Colchicine
Topics	Amino Acid Chloromethyl Ketones (pharmacology) Animals Animals, Newborn Anthracenes (pharmacology) Anti-Bacterial Agents (pharmacology) Apoptosis Apoptosis Regulatory Proteins Blotting, Western Bromodeoxyuridine (metabolism) CDC2-CDC28 Kinases (metabolism) Carrier Proteins (metabolism) Caspase 3 Caspases (metabolism) Cell Count Cell Survival Cells, Cultured Cerebellum (cytology, drug effects, physiology) Chromatin (metabolism) Colchicine (pharmacology) Cyclin E (metabolism) Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinases (metabolism) Cytochromes c (metabolism) Dose-Response Relationship, Drug Enzyme Inhibitors (pharmacology) Excitatory Amino Acid Agonists (pharmacology) Flavonoids (pharmacology) Flow Cytometry Immunohistochemistry Intracellular Signaling Peptides and Proteins JNK Mitogen-Activated Protein Kinases Kainic Acid (pharmacology) MAP Kinase Kinase 4 Microtubules (metabolism) Minocycline (pharmacology) Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism) Neurons (drug effects, physiology) Neuroprotective Agents (pharmacology) Piperidines (pharmacology) Purines (pharmacology) Rats Rats, Sprague-Dawley Roscovitine Time Factors Tubulin (metabolism)

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