Patients with medulloblastoma, the most common malignant childhood brain tumor, have poor overall survival despite intensive multimodal therapy and long-term survivors often suffer from irreversible adverse treatment effects. Cyclooxygenases (COX) catalyze the conversion of arachidonic acid to prostaglandins. COX-2 and prostaglandins have been shown to play important roles in several aspects of tumor development and progression. Medulloblastoma primary tumors and cell lines express high levels of cyclooxygenase-2 (COX-2), the prostanoid receptors (EP1-EP4) and produce prostaglandin E2, (PGE2), the major ligand for the prostanoid receptors. PGE2 and the EP2 receptor agonist, butaprost, stimulated medulloblastoma cell proliferation. On the other hand, treatment of medulloblastoma cells with nonsteroidal anti-inflammatory drugs (NSAID), inhibitors of COX suppressed PGE2 production and induced caspase-dependent apoptosis via the intrinsic mitochondrial pathway. Treatment of medulloblastoma cells with the EP1 receptor antagonist ONO-8713 and the EP3 receptor antagonist ONO-240 induced concentration-dependent cell death, whereas the EP4 antagonists ONO-208 and AH23848 were less effective in inhibiting medulloblastoma cell proliferation. These results suggest that an autocrine survival loop between PGE2 and its receptors stimulating tumor growth is present in medulloblastoma. COX-inhibitors significantly inhibited the growth of established human medulloblastoma xenografts in nude mice. Apoptosis was increased, proliferation was reduced and angiogenesis was inhibited in medulloblastoma tumors treated with COX-inhibitors. This study demonstrate that prostanoid production is important for medulloblastoma growth and that therapies targeting the prostanoid metabolic pathway are potentially beneficial and should be tested in clinical studies of patients with medulloblastoma.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA