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Marizomib activity as a single agent in malignant gliomas: ability to cross the
blood-brain barrier
#MMPMID26681765
Di K
; Lloyd GK
; Abraham V
; MacLaren A
; Burrows FJ
; Desjardins A
; Trikha M
; Bota DA
Neuro Oncol
2016[Jun]; 18
(6
): 840-8
PMID26681765
show ga
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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