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

• Published in: Clinical cancer research Vol. 14; no. 23; pp. 7717 - 7725
• Main Authors: GOLDHOFF, Patricia, WARRINGTON, Nicole M, LIMBRICK, David D, HOPE, Andrew, WOERNER, B. Mark, JACKSON, Erin, PERRY, Arie, PIWNICA-WORMS, David, RUBIN, Joshua B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2008
• Subjects: Adolescent; Adult; Aged; Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Biological and medical sciences; Bioluminescence; Blotting, Western; Brain Neoplasms - drug therapy; Brain Neoplasms - enzymology; Brain Neoplasms - radiotherapy; Brain Tumor; Cell Line, Tumor; Child; Child, Preschool; Combined Modality Therapy; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Female; Humans; Immunohistochemistry; Male; Medical sciences; Mice; Middle Aged; Neurology; PDE4A; Pharmacology. Drug treatments; Phosphodiesterase; Phosphodiesterase Inhibitors - administration & dosage; Rolipram; Rolipram - administration & dosage; Tumors of the nervous system. Phacomatoses; Xenograft Model Antitumor Assays; Intracranial; Nervous system diseases; Targeting; Rodentia; Cyclic AMP; Gene overexpression; Phosphodiesterase IV; Experimental study; Intracranial tumor; Cerebral disorder; Vertebrata; Target; Mammalia; Mouse; Animal; Central nervous system disease; Inhibitor; Inhibition
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0827

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, PDE4A1 was 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.