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

Neuropharmacology. 2003 Oct;45(5):672-83. doi: 10.1016/s0028-3908(03)00204-1.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Animals, Newborn
  • Anthracenes / pharmacology
  • Anti-Bacterial Agents / pharmacology
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Blotting, Western
  • Bromodeoxyuridine / metabolism
  • CDC2-CDC28 Kinases / metabolism
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspases / metabolism
  • Cell Count
  • Cell Survival
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / drug effects
  • Cerebellum / 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
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neurons / drug effects*
  • Neurons / physiology
  • Neuroprotective Agents / pharmacology*
  • Piperidines / pharmacology*
  • Purines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Roscovitine
  • Time Factors
  • Tubulin / metabolism

Substances

  • 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