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Mol Carcinog. 2017 May;56(5):1493-1500. doi: 10.1002/mc.22609. Epub 2017 Feb 8.

Brusatol overcomes chemoresistance through inhibition of protein translation.

Author information

1
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
2
Division of Medical Oncology. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
3
University of Arizona Cancer Center (UACC), University of Arizona, Tucson, Arizona.

Abstract

The NRF2 pathway activates a cell survival response when cells are exposed to xenobiotics or are under oxidative stress. Therapeutic activation of NRF2 can also be used prior to insult as a means of disease prevention. However, prolonged expression of NRF2 has been shown to protect cancer cells by inducing the metabolism and efflux of chemotherapeutics, leading to both intrinsic and acquired chemoresistance to cancer drugs. This effect has been termed the "dark side" of NRF2. In an effort to combat this chemoresistance, our group discovered the first NRF2 inhibitor, the natural product brusatol, however the mechanism of inhibition was previously unknown. In this report, we show that brusatol's mode of action is not through direct inhibition of the NRF2 pathway, but through the inhibition of both cap-dependent and cap-independent protein translation, which has an impact on many short-lived proteins, including NRF2. Therefore, there is still a need to develop a new generation of specific NRF2 inhibitors with limited toxicity and off-target effects that could be used as adjuvant therapies to sensitize cancers with high expression of NRF2.

KEYWORDS:

NRF2; brusatol; cancer; chemoresistance; protein translation

PMID:
28019675
PMCID:
PMC5404829
DOI:
10.1002/mc.22609
[Indexed for MEDLINE]
Free PMC Article

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