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4. Curcumin’s Metabolites, Tetrahydrocurcumin and Octahydrocurcumin, Possess Superior Anti-inflammatory Effects in vivo Through Suppression of TAK1-NF-κB Pathway

Author

Zhang, Zhen-Biao, primary, Luo, Dan-Dan, additional, Xie, Jian-Hui, additional, Xian, Yan-Fang, additional, Lai, Zheng-Quan, additional, Liu, Yu-Hong, additional, Liu, Wei-Hai, additional, Chen, Jian-Nan, additional, Lai, Xiao-Ping, additional, Lin, Zhi-Xiu, additional, and Su, Zi-Ren, additional

Published
2018
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10. Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity—implications for therapeutic targeting of Nrf2

Author

Olayanju, Adedamola, Copple, Ian M., Bryan, Holly K., Edge, George T., Sison, Rowena L., Wong, Min Wei, Lai, Zheng-Quan, Lin, Zhi-Xiu, Dunn, Karen, Sanderson, Christopher M., Alghanem, Ahmad F., Cross, Michael J., Ellis, Ewa C., Ingelman-Sundberg, Magnus, Malik, Hassan Z., Kitteringham, Neil R., Goldring, Christopher E., and Park, B. Kevin

Subjects
Chemical stress, Keap1, Toxicity, Physiology (medical), Brusatol, Hepatocyte, Free radicals, Cell defense, respiratory system, Biochemistry, digestive system, environment and public health, Nrf2
Abstract

The transcription factor Nrf2 regulates the basal and inducible expression of a battery of cytoprotective genes. Whereas numerous Nrf2-inducing small molecules have been reported, very few chemical inhibitors of Nrf2 have been identified to date. The quassinoid brusatol has recently been shown to inhibit Nrf2 and ameliorate chemoresistance in vitro and in vivo. Here, we show that brusatol provokes a rapid and transient depletion of Nrf2 protein, through a posttranscriptional mechanism, in mouse Hepa-1c1c7 hepatoma cells. Importantly, brusatol also inhibits Nrf2 in freshly isolated primary human hepatocytes. In keeping with its ability to inhibit Nrf2 signaling, brusatol sensitizes Hepa-1c1c7 cells to chemical stress provoked by 2,4-dinitrochlorobenzene, iodoacetamide, and N-acetyl-p-benzoquinone imine, the hepatotoxic metabolite of acetaminophen. 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.

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