Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier

Autor: Kaijun Di, Vivek Abraham, Ann MacLaren, Daniela A. Bota, Francis Burrows, Mohit Trikha, Annick Desjardins, G. Kenneth Lloyd
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Nude
Apoptosis
Mice
chemistry.chemical_compound
Lactones
0302 clinical medicine
Inbred BALB C
Cancer
proteasome inhibition
Mice
Inbred BALB C
Tumor
Bortezomib
Glioma
medicine.anatomical_structure
Oncology
5.1 Pharmaceuticals
Blood-Brain Barrier
030220 oncology & carcinogenesis
Basic and Translational Investigations
Proteasome Inhibitors
Biotechnology
medicine.drug
Oncology and Carcinogenesis
Mice
Nude
Blood–brain barrier
Cell Line
03 medical and health sciences
Rare Diseases
In vivo
Cell Line
Tumor
medicine
Animals
Pyrroles
Oncology & Carcinogenesis
marizomib
Animal
business.industry
chymotrypsin-like
Neurosciences
malignant glioma
blood-brain barrier
medicine.disease
Carfilzomib
Brain Disorders
Brain Cancer
Disease Models
Animal
Orphan Drug
030104 developmental biology
chemistry
Proteasome
Disease Models
Immunology
Cancer research
Proteasome inhibitor
Neurology (clinical)
business
Zdroj: Di, K; Lloyd, GK; Abraham, V; MacLaren, A; Burrows, FJ; Desjardins, A; et al.(2016). Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier. NEURO-ONCOLOGY, 18(6), 840-848. doi: 10.1093/neuonc/nov299. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/3td7095n
Neuro-oncology, vol 18, iss 6
DOI: 10.1093/neuonc/nov299.
Popis: Author(s): Di, Kaijun; Lloyd, G Kenneth; Abraham, Vivek; MacLaren, Ann; Burrows, Francis J; Desjardins, Annick; Trikha, Mohit; Bota, Daniela A | Abstract: BackgroundThe 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.MethodsThe 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.ResultsMarizomib 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 (g30%) 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 l .05) when treated with marizomib.ConclusionsThese 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.
Databáze: OpenAIRE
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