Journal
ACS CHEMICAL NEUROSCIENCE
Volume 11, Issue 13, Pages 1937-1943Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00093
Keywords
Largazole; histone deacetylases; BDNF; PAX6; brain cancer; neuroprotection
Funding
- National Institutes of Health [R01CA172310, R01CA138544]
- Debbie and Sylvia DeSantis Chair professorship
- [R50CA211487]
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Largazole is a potent class I selective histone deacetylase inhibitor prodrug with anticancer activity against solid tumors in preclinical models. Largazole possesses in vitro activity against glioblastoma multiforme (GBM) cells and sufficiently crosses the blood-brain barrier based on measurement of the active species, largazole thiol, to achieve therapeutically relevant concentrations in the mouse brain. The effective dose resulted in pronounced functional responses on the transcript level based on RNA sequencing and quantitative polymerase chain reaction after reverse transcription (RT-qPCR), revealing desirable expression changes of genes related to neuroprotection, including Bdnf and Pax6 upregulation, extending the applicability of largazole to the treatment of brain cancer and neurodegenerative disorders. The largazole-induced modulation of Pax6 unifies both activities, since Pax6 expression suppresses GBM proliferation and invasion and inversely correlates with GBM tumor grade, while it is also implicat ed in neurogenesis, neuronal plasticity, and cognitive ability. Our results suggest that largazole could be repurposed for diseases of the brain.
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