Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells

John A. Meyers, Josephine Taverna, Jorge Chaves, Anthony Makkinje, Adam Lerner

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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 (GRα) 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 GRα transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GRα mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GRα 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 GRα transcript levels in a dose-related manner, cotreatment with rolipram maintained GRα transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor - mediated up-regulation of GRα expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease.

Original languageEnglish (US)
Pages (from-to)4920-4927
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number16
DOIs
StatePublished - Aug 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells'. Together they form a unique fingerprint.

  • Cite this