title: Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo.
abstract: New therapies for glioblastoma (GBM) are needed, as five-year survival is <10%. The proteasome inhibitor marizomib (MRZ) has inhibitory and death-inducing properties unique from previous inhibitors such as bortezomib (BTZ), and has not been well examined in GBM. We evaluated the mechanism of death and in vivo properties of MRZ in GBM. The activation kinetics of initiator caspases 2, 8, and 9 were assessed using chemical and knockdown strategies to determine their contribution to cell death. Blood brain barrier permeance and proteasome inhibition by MRZ and BTZ were examined in an orthotopic GBM model. Blockade of caspase 9, relative to other caspases, was most protective against both MRZ and BTZ. Only MRZ increased the proteasome substrate p27 in orthotopic brain tumors after a single injection, while both MRZ and BTZ increased p21 levels after multiple treatments. Cleavage of caspase substrate lamin A was increased in orthotopic brain tumors from mice treated with MRZ or BTZ and the histone deacetylase inhibitor vorinostat. Our data indicate that MRZ induces caspase 9-dependent death in GBM, suggesting drug efficacy biomarkers and possible resistance mechanisms. MRZ reaches orthotopic brain tumors where it inhibits proteasome function and increases death in combination with vorinostat.
authors.affiliation: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030.|Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030.
authors.forename: Christa A
authors.initials: CA
authors.lastname: Manton
authors.affiliation: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030.|Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030.
authors.forename: Blake
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Melissa
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030.|Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030.
authors.forename: Cavan P
authors.initials: CP
authors.lastname: Bailey
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bouchier-Hayes
authors.affiliation: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030.|Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030.
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D000069286:Bortezomib / Q000008:administration & dosage; D020169:Caspases / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007783:Lactones / Q000008:administration & dosage*; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*
chemical_list: D014408:Biomarkers, Tumor; D007783:Lactones; D018809:Proliferating Cell Nuclear Antigen; D061988:Proteasome Inhibitors; D011758:Pyrroles; C413374:p27 antigen; D000069286:Bortezomib; C475865:marizomib; D020169:Caspases; D046988:Proteasome Endopeptidase Complex