(+)-Usnic acid modulates the Nrf2-ARE pathway in FaDu hypopharyngeal carcinoma cells

Abstract

Naturally occurring phytochemicals of different origin and structure, arctigenin, bergenin, usnic acid and xanthohumol, were shown to affect Nrf2 pathway in the context of various diseases, but their effect on this pathway in cancer cells was not extensively investigated. This study aimed to evaluate the effect of these compounds on Nrf2 expression and activation in hypopharyngeal FaDu squamous cell carcinoma cells. FaDu cells were treated with 2 or 10 μM arctigenin, bergenin, (+)-usnic acid or xanthohumol for 24 h. While arctigenin, bergenin, and xanthohumol did not affect either Nrf2 expression or activation, (+)-usnic acid treatment increased its transcript level and increased the nuclear/cytosol Nrf2 protein ratio—the measure of Nrf2 pathway activation. Consequently, (+)-usnic acid enhanced the transcription and translation of Nrf2 target genes: NQO1, SOD, and to a lesser extent, GSTP. The treatment of FaDu cells with (+)-usnic acid decreased both GSK-3β transcript and protein level, indicating its possible involvement in Nrf2 activation. All the tested compounds decreased Bax mRNA but did not change the level of Bax protein. (+)-Usnic acid tended to increase the percentage of early apoptotic cells and LC3 protein, autophagy marker. Significant induction of p53 also was observed after treatment with (+)-usnic acid. In summary, the results of this study indicate that low concentrations of (+)-usnic acid activate Nrf2 transcription factor, most probably as a result of ROS accumulation, but do not lead to FaDu hypopharyngeal carcinoma cells death.

ROS-Induced DNA-Damage and Autophagy in Oral Squamous Cell Carcinoma by Usnea barbata Oil Extract—An In Vitro Study

“…As a valuable representative of the Usnea genus, U. barbata has been used as phytomedicine for thousands of years [ 62 , 63 , 64 ]. Its biological potential is mainly attributed to a lipophilic phenolic compound, (+)- usnic acid [ 65 , 66 , 67 , 68 ]. Other minor secondary metabolites: phenolic acids [ 69 ], depsides, depsidones, and diphenyl ethers [ 70 ], could act synergistically with usnic acid in U. barbata extracts.…”

Usnic acid attenuates 7,12‐dimethylbenz[a] anthracene (DMBA) induced oral carcinogenesis through inhibiting oxidative stress, inflammation, and cell proliferation in male golden Syrian hamster model

“…[19] Furthermore, the antiproliferative properties of UA in many cancer cell line studies have recently been demonstrated in numerous research. [20][21][22][23][24][25] Therefore, UA is a potential candidate for cancer management; interestingly, it does not affect normal cells. [26] Polycyclic aromatic hydrocarbon of 7,12-dimethylbenz(a)-anthracene (DMBA) is extensively practiced in the experimental induction of site-specific cancer progression.…”