title: Sorafenib selectively depletes human glioblastoma tumor-initiating cells from primary cultures.
abstract: Glioblastomas are grade IV brain tumors characterized by high aggressiveness and invasiveness, giving patients a poor prognosis. We investigated the effects of the multi-kinase inhibitor sorafenib on six cultures isolated from human glioblastomas and maintained in tumor initiating cells-enriching conditions. These cell subpopulations are thought to be responsible for tumor recurrence and radio- and chemo-resistance, representing the perfect target for glioblastoma therapy. Sorafenib reduces proliferation of glioblastoma cultures, and this effect depends, at least in part, on the inhibition of PI3K/Akt and MAPK pathways, both involved in gliomagenesis. Sorafenib significantly induces apoptosis/cell death via downregulation of the survival factor Mcl-1. We provide evidence that sorafenib has a selective action on glioblastoma stem cells, causing enrichment of cultures in differentiated cells, downregulation of the expression of stemness markers required to maintain malignancy (nestin, Olig2 and Sox2) and reducing cell clonogenic ability in vitro and tumorigenic potential in vivo. The selectivity of sorafenib effects on glioblastoma stem cells is confirmed by the lower sensitivity of glioblastoma cultures after differentiation as compared with the undifferentiated counterpart. Since current GBM therapy enriches the tumor in cancer stem cells, the evidence of a selective action of sorafenib on these cells is therapeutically relevant, even if, so far, results from first phase II clinical trials did not demonstrate its efficacy.
authors: Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy.
authors: Elisa
authors: E
authors: Carra
authors: Federica
authors: F
authors: Barbieri
authors: Daniela
authors: D
authors: Marubbi
authors: Alessandra
authors: A
authors: Pattarozzi
authors: Roberto E
authors: RE
authors: Favoni
authors: Tullio
authors: T
authors: Florio
authors: Antonio
authors: A
authors: Daga
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D064231:Nestin; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000076104:Oligodendrocyte Transcription Factor 2; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014407:Tumor Cells, Cultured
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007381:Intermediate Filament Proteins; D020928:Mitogen-Activated Protein Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009419:Nerve Tissue Proteins; D064231:Nestin; D009536:Niacinamide; D000076104:Oligodendrocyte Transcription Factor 2; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D055748:SOXB1 Transcription Factors; D050796:STAT3 Transcription Factor; D000077157:Sorafenib; C577484:NES protein, human; C405708:OLIG2 protein, human; C527782:SOX2 protein, human; C494086:STAT3 protein, human
keywords: Mcl-1; glioblastoma; sorafenib; stemness; therapy; tumor initiating cells