Inhibition of PDE3, PDE4 and PDE7 potentiates glucocorticoid-induced apoptosis and overcomes glucocorticoid resistance in CEM T leukemic cells

• Published in: Biochemical pharmacology Vol. 79; no. 3; pp. 321 - 329
• Main Authors: Dong, Hongli, Zitt, Christof, Auriga, Cornelia, Hatzelmann, Armin, Epstein, Paul M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.02.2010; Elsevier
• Subjects: Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; cAMP; Cyclic Nucleotide Phosphodiesterases, Type 3 - physiology; Cyclic Nucleotide Phosphodiesterases, Type 4 - physiology; Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 7 - physiology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - physiology; Drug Synergism; Glucocorticoids; Glucocorticoids - pharmacology; Hematologic and hematopoietic diseases; Humans; Jurkat Cells; Leukemia; Leukemia, T-Cell - drug therapy; Leukemia, T-Cell - enzymology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Pharmacology. Drug treatments; Phosphodiesterase; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors - pharmacology; Tumor Cells, Cultured; Glucocorticoids; cAMP; Leukemia; Phosphodiesterase; Cyclic AMP; Malignant hemopathy; Glucocorticoid; Resistance; Cell death; T-Lymphocyte; AMP-3',5'; Inhibitor; Cancer; Apoptosis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.09.001

This paper concerns the targeting of cyclic nucleotide phosphodiesterases (PDEs) to induce apoptosis and overcome glucocorticoid resistance of leukemic cells. Stimulation of the cAMP signaling pathway has been shown to induce apoptosis and augment the effects of glucocorticoids in inducing apoptosis in leukemic cells. We recently reported that in primary B cell chronic lymphocytic leukemic (B-CLL) cells, apoptosis could be induced by stimulating the cAMP signaling pathway with a phosphodiesterase4 (PDE4) inhibitor alone; while in contrast, in the CEM T leukemic cell line, PDE4 inhibitors alone were ineffective, and concurrent stimulation of adenylyl cyclase was required to see effects [Tiwari et al. (2005) [3]]. We report here that in the CEM and Jurkat T leukemic cell lines, the most abundantly expressed PDEs are PDE3B, PDE4A, PDE4D, PDE7A, and PDE8A. Selective inhibition of PDE3, PDE4 or PDE7 alone produces little effect on cell viability, but inhibition of all three of these PDEs together dramatically enhances glucocorticoid-induced apoptosis in CEM cells, and overcomes glucocorticoid resistance in a glucocorticoid-resistant CEM cell line. These studies indicate that for some leukemic cell types, a desired therapeutic effect may be achieved by inhibiting more than one form of PDE.