title: Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway.
abstract: Human glioblastoma (GBM) cells are notorious for their resistance to apoptosis-inducing therapeutics. We have identified lanatoside C as a sensitizer of GBM cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death partly by upregulation of the death receptor 5. We show that lanatoside C sensitizes GBM cells to TRAIL-induced apoptosis in a GBM xenograft model in vivo. Lanatoside C on its own serves as a therapeutic agent against GBM by activating a caspase-independent cell death pathway. Cells treated with lanatoside C showed necrotic cell morphology with absence of caspase activation, low mitochondrial membrane potential, and early intracellular ATP depletion. In conclusion, lanatoside C sensitizes GBM cells to TRAIL-induced cell death and mitigates apoptosis resistance of glioblastoma cells by inducing an alternative cell death pathway. To our knowledge, this is one of the first examples of use of caspase-independent cell death inducers to trigger tumor regression in vivo. Activation of such mechanism may be a useful strategy to counter resistance of cancer cells to apoptosis.
authors.affiliation: Neuroscience Center and Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Badr
authors.forename: Thomas
authors.initials: T
authors.lastname: Wurdinger
authors.forename: Jonas
authors.initials: J
authors.lastname: Nilsson
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Niers
authors.forename: Michael
authors.initials: M
authors.lastname: Whalen
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007799:Lanatosides / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D007799:Lanatosides; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C018548:lanatoside C; D020169:Caspases