Targeted Inhibition of Cyclic AMP Phosphodiesterase-4 Promotes Brain Tumor Regression

Abstract

Purpose: As favorable outcomes from malignant brain tumors remain limited by poor survival and treatment-related toxicity, novel approaches to cure are essential. Previously, we identified the cyclic AMP phosphodiesterase-4 (PDE4) inhibitor Rolipram as a potent antitumor agent. Here, we investigate the role of PDE4 in brain tumors and examine the utility of PDE4 as a therapeutic target. Experimental Design: Immunohistochemistry was used to evaluate the expression pattern of a subfamily of PDE4, PDE4A, in multiple brain tumor types. To evaluate the effect of PDE4A on growth, a brain-specific isoform, PDE4A1was overexpressed in xenografts of Daoy medulloblastoma and U87 glioblastoma cells.To determine therapeutic potential of PDE4 inhibition, Rolipram, temozolomide, and radiation were tested alone and in combination on mice bearing intracranial U87 xenografts. Results: We found that PDE4A is expressed in medulloblastoma, glioblastoma, oligodendroglioma, ependymoma, and meningioma. Moreover, when PDE4A1 was overexpressed in Daoy medulloblastoma and U87 glioblastoma cells, in vivo doubling times were significantly shorter for PDE4A1-overexpressing xenografts compared with controls. In long-term survival and bioluminescence studies, Rolipram in combination with first-line therapy for malignant gliomas (temozolomide and conformal radiation therapy) enhanced the survival of mice bearing intracranial xenografts of U87 glioblastoma cells. Bioluminescence imaging indicated that whereas temozolomide and radiation therapy arrested intracranial tumor growth, the addition of Rolipram to this regimen resulted in tumor regression. Conclusions: This study shows that PDE4 is widely expressed in brain tumors and promotes their growth and that inhibition with Rolipram overcomes tumor resistance and mediates tumor regression.

BDNF and PDE4, but not the GRPR, Regulate Viability of Human Medulloblastoma Cells

“…Rolipram inhibits PDE4 leading to an increase in cellular levels of cAMP and stimulation of the cAMP/protein kinase A pathway. Goldhoff et al (2008) have recently shown that rolipram promoted tumor regression and enhanced survival in mice bearing U87-MG glioblastoma xenografts. In addition, these authors showed that PDE4A1 overexpression in medulloblastoma cells stimulated tumor growth.…”

Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF

“…13 Interestingly, PDE4 inhibitors (PDE4i) were shown to inhibit growth and chemotaxis and to increase differentiation and/or apoptosis in pancreatic cancer cells, colon cancer cells and malignant melanoma cells. [14][15][16] Inhibition of PDE4 by the selective inhibitor rolipram is shown to suppress tumor growth and augments the anti-tumor effects of chemotherapy and radiation therapy in medulloblastoma, glioblastoma 17 and in several hematological malignancies. 18 Why PDE4 isoforms are overexpressed in so many different tumor types remains elusive, but like other tumorigenesis factors, PDE4 isoforms may be regulated by changes in hypoxia.…”

Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways

“…cAMP degradation is regulated by a diverse set of phosphodiesterase (PDE) families (Caggiano and Kraig 1999;Lee et al 2002;Nakamura et al 1999). PDE4 is widely expressed in brain tumors and promotes their growth (Goldhoff et al 2008). Pharmacologic elevation of cAMP with the PDE4-specific inhibitor rolipram overcomes tumor resistance (Goldhoff et al 2008) and suppresses tumor cell growth in vitro.…”