Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells.
Glucocorticoids are integral to successful treatment of childhood acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. A large body of data indicates that in various model systems, elevation of cyclic adenosine monophosphate (cAMP) can potentiate glucocorticoid response, although this has not been well evaluated as a potential leukemia treatment. Although cAMP analogs have been studied, little data exist regarding the potential toxicity to leukemia cells of pharmacologic elevation of cAMP levels in leukemic blasts. Using MTT assays of cell proliferation on CEM ALL cells, we found that aminophylline and other nonspecific phosphodiesterase (PDE) inhibitors suppress cell growth. This effect is replicated by the PDE4-specific PDE inhibitor rolipram, but not by specific inhibitors of the PDE1 or PDE3 classes. We found that PDE inhibitors cause increased dexamethasone sensitivity and a synergistic effect with the adenylyl cyclase activator forskolin. We observed several important cellular characteristics associated with this treatment, including elevation of cAMP, induction of p53 and p21(WAF1/CIP1) proteins, G(1) and G(2)/M cell cycle arrest, and increased apoptosis. Sensitivity to forskolin and rolipram is shared by at least 2 pediatric ALL cell lines, CEM and Reh cells. Some cell lines derived from adult-type lymphoid malignancies also show sensitivity to this treatment. These findings suggest that PDE inhibitors have therapeutic potential in human ALL and characterize the molecular mechanisms that may be involved in this response.
Ogawa
Ryosuke
R
Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Streiff
Michael B
MB
Bugayenko
Artem
A
Kato
Gregory J
GJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000262:Adenylyl Cyclases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D020889:Rolipram / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D016159:Tumor Suppressor Protein p53; D005576:Colforsin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000262:Adenylyl Cyclases; D020889:Rolipram