Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression.
Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression.
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DOI：
10.1158/1078-0432.ccr-08-0827
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发表时间：
2008-12-01
期刊：
影响因子：
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通讯作者：
Rubin JB
中科院分区：
文献类型：
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作者：
Goldhoff P;Warrington NM;Limbrick DD Jr;Hope A;Woerner BM;Jackson E;Perry A;Piwnica-Worms D;Rubin JB
能够克服恶性脑肿瘤耐药性的疗法将是一个重大的临床进展。在此，我们研究cAMP磷酸二酯酶-4在刺激脑肿瘤生长中的作用以及cAMP磷酸二酯酶-4抑制剂在治疗恶性脑肿瘤中的治疗效用。环AMP磷酸二酯酶-4在人脑胶质和神经元谱系肿瘤中广泛表达，PDE 4A 1的强制表达加速颅内胶质母细胞瘤和髓母细胞瘤异种移植物生长。此外，靶向抑制PDE 4与标准放疗和化疗相结合，诱导了已建立的颅内胶质母细胞瘤异种移植物的独特消退。这些发现将PDE 4确定为脑肿瘤治疗的新分子靶点，并表明PDE 4抑制应在恶性脑肿瘤的临床试验中进行评估。由于恶性脑肿瘤的良好结局仍然受到生存率低和治疗相关毒性的限制，因此新的治疗方法至关重要。以前，我们确定了环AMP磷酸二酯酶-4（PDE 4）抑制剂Rolipram作为一种有效的抗肿瘤药物。在这里，我们研究了PDE 4在脑肿瘤中的作用，并研究了PDE 4作为治疗靶点的实用性。免疫组化法用于评估PDE 4亚家族PDE 4A在多种脑肿瘤类型中的表达模式。为了评估PDE 4A对生长的影响，在Daoy髓母细胞瘤和U87胶质母细胞瘤细胞的异种移植物中过表达脑特异性同种型PDE 4A 1。为了确定PDE 4抑制的治疗潜力，在携带颅内U87异种移植物的小鼠中单独和组合测试咯利普兰、替莫唑胺和辐射。我们发现PDE 4A在髓母细胞瘤、胶质母细胞瘤、少突胶质细胞瘤、室管膜瘤和脑膜瘤中表达。此外，当PDE 4A 1在Daoy髓母细胞瘤和U87胶质母细胞瘤细胞中过表达时，与对照相比，PDE 4A 1过表达异种移植物的体内倍增时间显著缩短。在长期生存和生物发光研究中，Rolipram联合恶性胶质瘤的一线治疗（替莫唑胺和适形放射治疗）提高了携带U87胶质母细胞瘤细胞颅内异种移植物的小鼠的生存率。生物发光成像表明，虽然替莫唑胺和放射治疗阻止了颅内肿瘤的生长，但在该方案中加入咯利普兰导致肿瘤消退。这项研究表明，PDE 4在脑肿瘤中广泛表达并促进其生长，并且Rolipram的抑制克服了肿瘤抗性并介导了肿瘤消退。
Therapies that can overcome the resistance of malignant brain tumors would be a major clinical advance. Here, we investigate the role of cAMP Phosphodiesterase-4 in stimulating brain tumor growth and the therapeutic utility of cAMP Phosphodiesterase-4 inhibition in the treatment of malignant brain tumors. Cyclic AMP Phosphodiesterase-4 was widely expressed in human brain tumors of glial and neuronal lineage, and forced expression of PDE4A1 accelerated intracranial glioblastoma and medulloblastoma xenograft growth. Moreover, targeted inhibition of PDE4, in combination with standard radiation and chemotherapy, induced a unique regression of established intracranial glioblastoma xenografts. These findings identify PDE4 as a novel molecular target for brain tumor therapy and indicate that PDE4 inhibition should be evaluated in clinical trials for malignant brain tumors. 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 anti-tumor agent. Here, we investigate the role of PDE4 in brain tumors and examine the utility of PDE4 as a therapeutic target. 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. 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 to 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 while temozolomide and radiation therapy arrested intracranial tumor growth, the addition of Rolipram to this regimen resulted in tumor regression. 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.