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Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2.

Olayanju A, Copple IM, Bryan HK, Edge GT, Sison RL, Wong MW, Lai ZQ, Lin ZX, Dunn K, Sanderson CM, Alghanem AF, Cross MJ, Ellis EC, Ingelman-Sundberg M, Malik HZ, Kitteringham NR, Goldring CE, Park BK - Free Radic. Biol. Med. (2014)

Bottom Line: The inhibitory effect of brusatol toward Nrf2 is shown to be independent of its repressor Keap1, the proteasomal and autophagic protein degradation systems, and protein kinase signaling pathways that are known to modulate Nrf2 activity, implying the involvement of a novel means of Nrf2 regulation.These findings substantiate brusatol as a useful experimental tool for the inhibition of Nrf2 signaling and highlight the potential for therapeutic inhibition of Nrf2 to alter the risk of adverse events by reducing the capacity of nontarget cells to buffer against chemical and oxidative insults.These data will inform a rational assessment of the risk:benefit ratio of inhibiting Nrf2 in relevant therapeutic contexts, which is essential if compounds such as brusatol are to be developed into efficacious and safe drugs.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

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Brusatol sensitizes mammalian cells to chemical stress. ATP content in Hepa-1c1c7 cells exposed to 300 nM brusatol for the indicated times, followed by the indicated concentrations of (A) DNCB for 6 h, (B) IAA for 6 h, or (C) NAPQI for 12 h is shown. ATP levels are expressed as a percentage of the ATP content of vehicle-exposed cells. Data represent the mean + SD of n=3 independent experiments. Statistical analysis was performed using an unpaired t test (*P<0.05, **P<0.01 vs vehicle control).
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f0025: Brusatol sensitizes mammalian cells to chemical stress. ATP content in Hepa-1c1c7 cells exposed to 300 nM brusatol for the indicated times, followed by the indicated concentrations of (A) DNCB for 6 h, (B) IAA for 6 h, or (C) NAPQI for 12 h is shown. ATP levels are expressed as a percentage of the ATP content of vehicle-exposed cells. Data represent the mean + SD of n=3 independent experiments. Statistical analysis was performed using an unpaired t test (*P<0.05, **P<0.01 vs vehicle control).

Mentions: In light of our data demonstrating the ability of brusatol to inhibit Nrf2 signaling, and given the well-defined role of Nrf2 in regulating the activity of cytoprotective processes in mammalian cells, we sought to test the hypothesis that brusatol-mediated depletion of Nrf2 would sensitize Hepa-1c1c7 cells to the deleterious effects of chemical stress provoked by model electrophiles. Indeed, pretreatment of cells with brusatol enhanced the cytotoxicity elicited by DNCB, IAA, and NAPQI (Figs. 5A–C). Notably, increasing the duration of the brusatol pretreatment period resulted in a greater potentiation of cytotoxicity in each case (Figs. 5A–C). Therefore, these data indicate that brusatol is capable of sensitizing mammalian cells to chemical stress.


Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2.

Olayanju A, Copple IM, Bryan HK, Edge GT, Sison RL, Wong MW, Lai ZQ, Lin ZX, Dunn K, Sanderson CM, Alghanem AF, Cross MJ, Ellis EC, Ingelman-Sundberg M, Malik HZ, Kitteringham NR, Goldring CE, Park BK - Free Radic. Biol. Med. (2014)

Brusatol sensitizes mammalian cells to chemical stress. ATP content in Hepa-1c1c7 cells exposed to 300 nM brusatol for the indicated times, followed by the indicated concentrations of (A) DNCB for 6 h, (B) IAA for 6 h, or (C) NAPQI for 12 h is shown. ATP levels are expressed as a percentage of the ATP content of vehicle-exposed cells. Data represent the mean + SD of n=3 independent experiments. Statistical analysis was performed using an unpaired t test (*P<0.05, **P<0.01 vs vehicle control).
© Copyright Policy - CC BY
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4291150&req=5

f0025: Brusatol sensitizes mammalian cells to chemical stress. ATP content in Hepa-1c1c7 cells exposed to 300 nM brusatol for the indicated times, followed by the indicated concentrations of (A) DNCB for 6 h, (B) IAA for 6 h, or (C) NAPQI for 12 h is shown. ATP levels are expressed as a percentage of the ATP content of vehicle-exposed cells. Data represent the mean + SD of n=3 independent experiments. Statistical analysis was performed using an unpaired t test (*P<0.05, **P<0.01 vs vehicle control).
Mentions: In light of our data demonstrating the ability of brusatol to inhibit Nrf2 signaling, and given the well-defined role of Nrf2 in regulating the activity of cytoprotective processes in mammalian cells, we sought to test the hypothesis that brusatol-mediated depletion of Nrf2 would sensitize Hepa-1c1c7 cells to the deleterious effects of chemical stress provoked by model electrophiles. Indeed, pretreatment of cells with brusatol enhanced the cytotoxicity elicited by DNCB, IAA, and NAPQI (Figs. 5A–C). Notably, increasing the duration of the brusatol pretreatment period resulted in a greater potentiation of cytotoxicity in each case (Figs. 5A–C). Therefore, these data indicate that brusatol is capable of sensitizing mammalian cells to chemical stress.

Bottom Line: The inhibitory effect of brusatol toward Nrf2 is shown to be independent of its repressor Keap1, the proteasomal and autophagic protein degradation systems, and protein kinase signaling pathways that are known to modulate Nrf2 activity, implying the involvement of a novel means of Nrf2 regulation.These findings substantiate brusatol as a useful experimental tool for the inhibition of Nrf2 signaling and highlight the potential for therapeutic inhibition of Nrf2 to alter the risk of adverse events by reducing the capacity of nontarget cells to buffer against chemical and oxidative insults.These data will inform a rational assessment of the risk:benefit ratio of inhibiting Nrf2 in relevant therapeutic contexts, which is essential if compounds such as brusatol are to be developed into efficacious and safe drugs.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Show MeSH
Related in: MedlinePlus