The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells

Upregulation of the cAMP/protein kinase A (PKA) pathway has been shown to result in decreased proliferation, increased differentiation, and subsequent apoptosis of malignant glioma cells. Conventional cAMP analogs, however, are difficult to use in a clinical setting. Therefore, we investigated the e...

Full description

Saved in:
Bibliographic Details
Published in:Cancer biology & therapy 2002-05, Vol.1 (3), p.268-276
Main Authors: Chen, Thomas C, Wadsten, Pia, Su, Susan, Rawlinson, Neal, Hofman, Florence M, Hill, Colin K, Schönthal, Axel H
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
Apoptosis - drug effects
Blotting, Western
Cell Cycle Proteins - metabolism
Cell Differentiation - drug effects
Cyclic AMP - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclins - drug effects
Cyclins - metabolism
DNA, Neoplasm - metabolism
Enzyme Activation - physiology
Enzyme Inhibitors - pharmacology
G1 Phase - drug effects
Glioma - pathology
Humans
Neoplasm Invasiveness
Phosphodiesterase Inhibitors - pharmacology
Promoter Regions, Genetic
Response Elements
Rolipram - pharmacology
Transfection
Tumor Cells, Cultured
Tumor Suppressor Proteins - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Upregulation of the cAMP/protein kinase A (PKA) pathway has been shown to result in decreased proliferation, increased differentiation, and subsequent apoptosis of malignant glioma cells. Conventional cAMP analogs, however, are difficult to use in a clinical setting. Therefore, we investigated the effects of rolipram, a drug that has undergone clinical trials as an antidepressant and has also been proposed as a treatment for multiple sclerosis. Rolipram acts as a specific inhibitor of type IV phosphodiesterase (PDE4), leading to increased intracellular levels of cAMP. We report that the inhibition of PDE4 by rolipram results in the activation of the cAMP/PKA pathway, with potent stimulation of a reporter gene containing a cAMP-responsive element in its promoter region. Further, treatment of the human glioma cell line A-172 with rolipram results in increased expression of the cell cycle inhibitors p21(Cip1) and p27(KiP1), and decreased activity of cdk2, a cyclin-dependent kinase essential for cell cycle progression. As a result, the proliferation of A-172 cells is inhibited, with induction of a Gl block. Eventually, rolipram-treated A-172 cells undergo differentiation, which is followed by apoptotic cell death. As we observe this effect with other glioma cell cultures as well, our results suggest that rolipram could prove useful as a novel differentiating agent with both cytostatic and cytotoxic potential in the treatment of malignant gliomas.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.80