title: Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier.
abstract: The proteasome plays a vital role in the physiology of glioblastoma (GBM), and proteasome inhibition can be used as a strategy for treating GBM. Marizomib is a second-generation, irreversible proteasome inhibitor with a more lipophilic structure that suggests the potential for penetrating the blood-brain barrier. While bortezomib and carfilzomib, the 2 proteasome inhibitors approved for treatment of multiple myeloma, have little activity against malignant gliomas in vivo, marizomib could be a novel therapeutic strategy for primary brain tumors.
  
  
  
  The in-vitro antitumor activity of marizomib was studied in glioma cell lines U-251 and D-54. The ability of marizomib to cross the blood-brain barrier and regulate proteasome activities was evaluated in cynomolgus monkeys and rats. The antitumor effect of marizomib in vivo was tested in an orthotopic xenograft model of human GBM.
  
  
  
  Marizomib inhibited the proteasome activity, proliferation, and invasion of glioma cells. Meanwhile, free radical production and apoptosis induced by marizomib could be blocked by antioxidant N-acetyl cysteine. In animal studies, marizomib distributed into the brain at 30% of blood levels in rats and significantly inhibited (>30%) baseline chymotrypsin-like proteasome activity in brain tissue of monkeys. Encouragingly, the immunocompromised mice, intracranially implanted with glioma xenografts, survived significantly longer than the control animals (P < .05) when treated with marizomib.
  
  
  
  These preclinical studies demonstrated that marizomib can cross the blood-brain barrier and inhibit proteasome activity in rodent and nonhuman primate brain and elicit a significant antitumor effect in a rodent intracranial model of malignant glioma.
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: Kaijun
authors.initials: K
authors.lastname: Di
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Lloyd
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: Vivek
authors.initials: V
authors.lastname: Abraham
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: Ann
authors.initials: A
authors.lastname: MacLaren
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Burrows
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: Mohit
authors.initials: M
authors.lastname: Trikha
authors.affiliation: University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Bota
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005910:Glioma / Q000188:drug therapy*; D007783:Lactones / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; C475865:marizomib
keywords: blood-brain barrier; chymotrypsin-like; malignant glioma; marizomib; proteasome inhibition