title: Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells.
abstract: The present studies were designed to determine whether the multi-kinase inhibitor sorafenib (Nexavar) interacted with histone deacetylase inhibitors to kill glioblastoma and medulloblastoma cells. In a dose-dependent fashion sorafenib lethality was enhanced in multiple genetically disparate primary human glioblastoma isolates by the HDAC inhibitor sodium valproate (Depakote). Drug exposure reduced phosphorylation of p70 S6K and of mTOR. Similar data to that with valproate were also obtained using the HDAC inhibitor vorinostat (Zolinza). Sorafenib and valproate also interacted to kill medulloblastoma and PNET cell lines. Treatment with sorafenib and HDAC inhibitors radio-sensitized both GBM and medulloblastoma cell lines. Knock down of death receptor (CD95) expression protected GBM cells from the drug combination, as did overexpression of c-FLIP-s, BCL-XL and dominant negative caspase 9. Knock down of PDGFRα recapitulated the effect of sorafenib in combination with HDAC inhibitors. Collectively, our data demonstrate that the combination of sorafenib and HDAC inhibitors kills through activation of the extrinsic pathway, and could represent a useful approach to treat CNS-derived tumors.
authors.affiliation: Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.forename: Gary
authors.initials: G
authors.lastname: Tye
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016543:Central Nervous System Neoplasms / Q000201:enzymology* / Q000235:genetics; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D056572:Histone Deacetylase Inhibitors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D019014:fas Receptor; D009536:Niacinamide; D000077157:Sorafenib