Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets.
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Baryawno N, Sveinbjornsson B, Eksborg S, Orrego A, Segerstrom L, Oqvist CO, Holm S, Gustavsson B, Kagedal B, Kogner P, Johnsen JI
Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets.
Neuro Oncol. 2008 Oct;10(5):661-74. doi: 10.1215/15228517-2008-035. Epub 2008 Aug 20.
- PubMed ID
- 18715952 [ View in PubMed]
- Abstract
Prostaglandin E(2) (PGE(2)) has been shown to play important roles in several aspects of tumor development and progression. PGE(2) is synthesized from arachidonic acid by cyclooxygenases (COX) and prostaglandin E synthases (PGES) and mediates its biological activity through binding to the four prostanoid receptors EP(1) through EP(4). In this study, we show for the first time that medulloblastoma (MB), the most common malignant childhood brain tumor, expresses high levels of COX-2, microsomal prostaglandin E synthase-1, and EP(1) through EP(4) and secretes PGE(2). PGE(2) and the EP(2) receptor agonist butaprost stimulated MB cell proliferation. Treatment of MB cells with COX inhibitors suppressed PGE(2) production and induced caspase-dependent apoptosis. Similarly, specific COX-2 silencing by small interfering RNA inhibited MB cell growth. EP(1) and EP(3) receptor antagonists ONO-8713 and ONO-AE3-240, but not the EP(4) antagonists ONO-AE3-208 and AH 23848, inhibited tumor cell proliferation, indicating the significance of EP(1) and EP(3) but not EP(4) for MB growth. Administration of COX inhibitors at clinically achievable nontoxic concentrations significantly inhibited growth of established human MB xenografts. Apoptosis was increased, proliferation was reduced, and angiogenesis was inhibited in MBs treated with COX inhibitors. This study suggests that PGE(2) is important for MB growth and that therapies targeting the prostanoid metabolic pathway are potentially beneficial and should be tested in clinical settings for treatment of children with MB.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Dinoprostone Prostaglandin E2 receptor EP1 subtype Protein Humans YesAgonistDetails Dinoprostone Prostaglandin E2 receptor EP2 subtype Protein Humans YesAgonistDetails Dinoprostone Prostaglandin E2 receptor EP3 subtype Protein Humans YesAgonistDetails Dinoprostone Prostaglandin E2 receptor EP4 subtype Protein Humans YesAgonistDetails