Tumor-growth–promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets

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.

Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target

“…The origin of the cells, culture conditions, and viability assays of human medulloblastoma and supratentorial primitive neuroectodermal cell lines have been described (14). Human prostate cells, pancreas adenocarcinoma cells, PC-3 and BxPC-3 cells, human fibroblasts (MRC-5), and K562 cells (human chronic myelogenous leukemia) were grown in RPMI medium supplemented with 10% heat-inactivated fetal bovine serum, 2 mM l-glutamine, 100 IU/ml penicillin G, and 100 μg/ ml streptomycin (Life Technologies).…”

“…Viability assays (MTT) were as described previously (14). Tumorigenic potential was assessed with an in vitro clonogenic assay as described (14).…”

“…Viability assays (MTT) were as described previously (14). Tumorigenic potential was assessed with an in vitro clonogenic assay as described (14). Briefly, cells were infected with HCMV VR1814 (MOI of 10) for 3 days and reseeded in triplicate at 150 cells/well in 50-mm 2 well Cell + plates (Sarstedt); control cells were not infected.…”

“…For unknown reasons, many tumors, including medulloblastomas, express COX-2, and inhibition of PGE 2 synthesis with nonsteroidal antiinflammatory drugs induces apoptosis in medulloblastoma cell lines and significantly inhibits the growth of medulloblastomas in vivo (14). Aspirin reduces the incidence and growth of various cancer forms in animal models (15,16), an effect that may be mediated at least in part by inhibition of COX-2 enzymes, resulting in decreased production of prostaglandins and other inflammatory mediators.…”

Embryonal neural tumours and cell death

“…Two transcriptional repressors of survivin, YM155 and EM-1421, have recently entered clinical trials but so far only modest anti-tumour activity has been obtained [31]. One perhaps even more interesting finding is that several other anti-cancer agents like ARC (4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide), histone deacetylase inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs), shown to be effective apoptosis inducers in preclinical medulloblastoma and neuroblastoma therapy, also indirectly inhibit the expression of survivin [138][139][140][141][142][143].…”