Abstract
PDE7A is a recently described 3',5'-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) whose expression has been detected in T-cells. As treatment with the methylxanthine theophylline, a nonspecific PDE inhibitor, induces apoptosis in leukemic cells from patients with the B-lineage malignancy chronic lymphocytic leukemia (CLL), we sought to determine if PDE7A was a target of theophylline therapy in such cells. Western analysis revealed expression of PDE7A in normal human splenic B-cells, primary CLL cells, and in a CLL-derived cell line (WSU-CLL). Among the six cAMP PDEs (PDE1B, PDE3B, PDE4A, PDE4B, PDE4D, and PDE7) examined in WSU-CLL, only PDE7A levels were augmented by treatment with methylxanthines. The activity of PDE7A isolated from the WSU-CLL cell line by immunoprecipitation was inhibited by theophylline and IBMX with IC50 values of 343.5 and 8.6 microM, respectively. WSU-CLL PDE7A was also up-regulated by a novel specific inhibitor (IC242), which inhibits PDE7A from WSU-CLL cells with an IC50 value of 0.84 microM. IC242-mediated up-regulation of PDE7A was blocked by the protein kinase A (PKA) inhibitor H-89.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-Methyl-3-isobutylxanthine / pharmacology
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
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3',5'-Cyclic-AMP Phosphodiesterases / genetics
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
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B-Lymphocytes / cytology
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B-Lymphocytes / drug effects
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B-Lymphocytes / enzymology*
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Cells, Cultured
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Colforsin / pharmacology
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Cyclic AMP / metabolism*
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Dose-Response Relationship, Drug
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Humans
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Intracellular Fluid
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Leukemia, Lymphocytic, Chronic, B-Cell
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Leukemia-Lymphoma, Adult T-Cell
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Phosphodiesterase Inhibitors / pharmacology
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Purinergic P1 Receptor Antagonists
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Spleen / cytology
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Theophylline / pharmacology
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Tumor Cells, Cultured
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Up-Regulation*
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Xanthines / pharmacology
Substances
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Phosphodiesterase Inhibitors
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Purinergic P1 Receptor Antagonists
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Xanthines
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Colforsin
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1,3-dipropyl-8-cyclopentylxanthine
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Theophylline
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Cyclic AMP
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE3B protein, human
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PDE4A protein, human
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PDE4B protein, human
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PDE4D protein, human
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1-Methyl-3-isobutylxanthine