Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis.
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.
Jorda
Elvira G
EG
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.
Verdaguer
Ester
E
Canudas
Anna M
AM
Jiménez
Andrés
A
Bruna
Alejandra
A
Caelles
Carme
C
Bravo
Ramona
R
Escubedo
Elena
E
Pubill
David
D
Camarasa
Jordi
J
Pallàs
Mercè
M
Camins
Antoni
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002843:Chromatin / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology*; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D007608:Kainic Acid / Q000494:pharmacology; D048670:MAP Kinase Kinase 4; D008870:Microtubules / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000873:Anthracenes; D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D002843:Chromatin; D019927:Cyclin E; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D010880:Piperidines; D011687:Purines; D014404:Tubulin; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C101296:prostate apoptosis response-4 protein; D000077546:Roscovitine; C432165:pyrazolanthrone; C077990:alvocidib; D045304:Cytochromes c; D051360:Cyclin-Dependent Kinase 5; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495907:Cdk5 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D008911:Minocycline; D001973:Bromodeoxyuridine; D007608:Kainic Acid; D003078:Colchicine