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 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.
Chen
Thomas C
TC
LAC/USC Medical Center, Department of Neurosurgery, Pathology, University of Southern California, 1200 N. State St., Suite 5046, Los Angeles, CA 90033, USA. tcchen@hsc.usc.edu
Wadsten
Pia
P
Su
Susan
S
Rawlinson
Neal
N
Hofman
Florence M
FM
Hill
Colin K
CK
Schönthal
Axel H
AH
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D020889:Rolipram / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram