Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21WAF1/CIP1 proteins in human acute lymphoblastic leukemia cells

被引:73
作者
Ogawa, R
Streiff, MB
Bugayenko, A
Kato, GJ
机构
[1] Johns Hopkins Univ, Dept Pediat, Div Hematol, Sch Med, Baltimore, MD USA
[2] Johns Hopkins Univ, Dept Med, Baltimore, MD USA
[3] Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA
关键词
D O I
10.1182/blood.V99.9.3390
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 rollpram, 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 rollpram 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. (C) 2002 by The American Society of Hematology.
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页码:3390 / 3397
页数:8
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