title: Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas.
abstract: Moving from the evidence that activation of type 4 metabotropic glutamate (mGlu4) receptors inhibits proliferation and promotes differentiation of cerebellar granule cell neuroprogenitors, we examined the expression and function of mGlu4 receptors in medulloblastoma cells. mGlu4 receptors were expressed in 46 of 60 human medulloblastoma samples. Expression varied in relation to the histotype (nodular desmoplastic>classic>>large-cell anaplastic) and was inversely related to tumor severity, spreading, and recurrence. mGlu4 receptors were also found in D283med, D341med, and DAOY medulloblastoma cell lines, where receptor activation with the selective enhancer PHCCC inhibited adenylyl cyclase and the phosphatidylinositol-3-kinase pathway without affecting the mitogen-activated protein kinase, Sonic Hedgehog, and Wnt pathways. Interestingly, mGlu4 receptor activation reduced DNA synthesis and cell proliferation in all three cell lines. This effect was abrogated by the phosphatidylinositol-3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]. In in vivo experiments, repeated subcutaneous injections of N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) reduced the growth of D283med and DAOY cell xenografts in nude mice. More remarkably, subcutaneous or intracranial injections of PHCCC during the first week of life prevented the development of medulloblastomas in mice lacking one Patched-1 allele and x-irradiated 1 d after birth. These data suggest that mGlu4 receptor enhancers are promising drugs for the treatment of medulloblastomas.
authors.affiliation: Department of Human Physiology and Pharmacology, University of Rome La Sapienza, 00185 Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Iacovelli
authors.forename: Antonietta
authors.initials: A
authors.lastname: Arcella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Paola
authors.initials: P
authors.lastname: Spinsanti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Caruso
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Mara
authors.initials: M
authors.lastname: D'Onofrio
authors.forename: Felice
authors.initials: F
authors.lastname: Giangaspero
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D001578:Benzopyrans; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4