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In vitro and in vivo characterization of a novel hedgehog signaling antagonist in human glioblastoma cell lines
Author(s) -
Ferruzzi Pietro,
Mennillo Federica,
De Rosa Antonella,
Giordano Cinzia,
Rossi Marco,
Benedetti Giovanni,
Magrini Roberta,
Mohr Gal.la Pericot,
Miragliotta Vincenzo,
Magi Letizia,
Mori Elisa,
Thomas Russell,
Tunici Patrizia,
Bakker Annette
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27349
Subject(s) - smoothened , neurosphere , hedgehog signaling pathway , temozolomide , cancer research , sonic hedgehog , hedgehog , biology , cell culture , population , microbiology and biotechnology , signal transduction , in vitro , medicine , glioblastoma , adult stem cell , biochemistry , genetics , endothelial stem cell , environmental health
Glioblastoma multiforme (GBM) is composed of heterogeneous and genetically different cells, which are highly invasive and motile. The standard chemotherapeutic agent, temozolomide, affects GBM cell proliferation but is generally unable to prevent tumor recurrence. Hedgehog pathway activation has been reported to be relevant in GBM and different pharmacological pathway modulators have been identified. We report that by growing a commercially available recurrent GBM cell line (DBTRG‐05MG) without serum and in the presence of defined growth factors; we obtained a less differentiated cell population, growing in suspension as neurospheres, in which the Hedgehog pathway is activated. Furthermore, the expression profile of Hedgehog pathway components found in DBTRG‐05MG neurospheres is similar to primary stem‐like cells derived from recurrent GBM patients. We report the effect of our novel specific Smoothened receptor antagonist (SEN450) on neurosphere growing cells and compared its effect to that of well known benchmark compounds. Finally, we showed that SEN450 is both antiproliferative on its own and further reduces tumor volume after temozolomide pretreatment in a mouse xenograft model using DBTRG‐05MG neurosphere cells. Altogether our data indicate that the Hedgehog pathway is not irreversibly switched off in adherent cells but can be reactivated when exposed to well‐defined culture conditions, thus restoring the condition observed in primary tumor‐derived material, and that pharmacological modulation of this pathway can have profound influences on tumor proliferation. Therefore, pharmacological inhibition of the Hedgehog pathway is a potentially useful therapeutic approach in GBM.