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Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells

Authors' Affiliations: ¹ Evans Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, and ² Department of Pathology, Boston University School of Medicine, Boston, Massachusetts

Requests for reprints: Adam Lerner, Section of Hematology/Oncology, Evans Department of Medicine, Evans Biomedical Research Center 420, 650 Albany Street, Boston, MA 02118. Phone: 617-638-7504; E-mail: lernwara{at}bu.edu.

Type 4 cyclic AMP (cAMP) phosphodiesterase (PDE4) inhibitors, a class of compounds in clinical development that activate cAMP-mediated signaling by inhibiting cAMP catabolism, offer a feasible means by which to potentiate glucocorticoid-mediated apoptosis in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). In this study, we show that PDE4 inhibitors up-regulate glucocorticoid receptor (GR) transcript levels in B-CLL cells but not T-CLL cells or Sezary cells or normal circulating T cells, B cells, monocytes, or neutrophils. Because GR transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GR mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GR transcription. Rolipram treatment increases levels of transcripts derived from the 1A3 promoter to a greater extent than the 1B promoter. Treatment of B-CLL cells with two other PDE4 inhibitors currently in clinical development also augments GR transcript levels and glucocorticoid-mediated apoptosis. Washout studies show that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that GR up-regulation occurs. Although treatment of B-CLL cells with glucocorticoids reduces basal GR transcript levels in a dose-related manner, cotreatment with rolipram maintained GR transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor–mediated up-regulation of GR expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease.

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				J. A. Meyers, D. W. Su, and A. Lerner Chronic Lymphocytic Leukemia and B and T Cells Differ in Their Response to Cyclic Nucleotide Phosphodiesterase Inhibitors J. Immunol., May 1, 2009; 182(9): 5400 - 5411. [Abstract] [Full Text] [PDF]