title: HDAC inhibitors enhance the lethality of low dose salinomycin in parental and stem-like GBM cells.
abstract: The present studies determined whether the antibiotic salinomycin interacted with HDAC inhibitors to kill primary human GBM cells. Regardless of PTEN, ERBB1, or p53 mutational status salinomycin interacted with HDAC inhibitors in a synergistic fashion to kill GBM cells. Inhibition of CD95/Caspase 8 or of CD95/RIP-1/AIF signaling suppressed killing by the drug combination. Salinomycin increased the levels of autophagosomes that correlated with increased p62 and LC3II levels; valproate co-treatment correlated with reduced LC3II and p62 expression, and increased caspase 3 cleavage. Molecular inhibition of autophagosome formation was protective against drug exposure. The drug combination enhanced eIF2α phosphorylation and decreased expression of MCL-1 and phosphorylation of mTOR and p70 S6K. Activation of p70 S6K or mTOR promoted cell survival in the face of combined drug exposure. Overexpression of BCL-XL or c-FLIP-s was protective. Collectively our data demonstrate that the lethality of low nanomolar concentrations of salinomycin are enhanced by HDAC inhibitors in GBM cells and that increased death receptor signaling together with reduced mitochondrial function are causal in the combinatorial drug necro-apoptotic killing effect.
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Roberts
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Conley
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ridder
authors.affiliation: Department of Medicine; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.affiliation: Department of Medicine; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009336:Necrosis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011714:Pyrans / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*; D000077337:Vorinostat; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011714:Pyrans; D014635:Valproic Acid; D000077337:Vorinostat; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: AIF; HDAC inhibitor; RIP-1; autophagy; glioblastoma; mTOR; necro-apoptosis; salinomycin; stem cell