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Ref Type Journal Article
PMID (26804704)
Authors Manton CA, Johnson B, Singh M, Bailey CP, Bouchier-Hayes L, Chandra J
Title Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo.
Journal Scientific reports
Vol 6
Issue
Date 2016
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown glioblastoma multiforme not applicable Marizomib + Vorinostat Preclinical Actionable In a preclinical study, glioblastoma cells treated with a combination of Zolinza (vorinostat) and Marizomib resulted in a synergistic effect, demonstrating decreased cell viability, DNA fragmentation and elevated caspase 9 activity in both culture and xenograft models (PMID: 26804704). 26804704
Unknown unknown glioblastoma multiforme not applicable Bortezomib + Vorinostat Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Zolinza (vorinostat) and Velcade (bortezomib) synergized to decrease cell viability, DNA fragmentation and elevate caspase 9 activity in several human glioblastoma cell lines in culture and in xenograft models of one human glioblastoma cell line (PMID: 26804704). 26804704
Unknown unknown glioblastoma multiforme not applicable Bortezomib + Panobinostat Preclinical Actionable In a preclinical study, glioblastoma cells treated with a combination of Farydak (panobinostat) and Velcade (bortezomib) resulted in a synergistic effect, demonstrating decreased cell viability in culture (PMID: 26804704). 26804704
Unknown unknown glioblastoma multiforme not applicable Marizomib + Panobinostat Preclinical Actionable In a preclinical study, glioblastoma cells treated with a combination of Farydak (panobinostat) and Marizomib resulted in a synergistic effect, demonstrating decreased cell viability in culture (PMID: 26804704). 26804704