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Open AccessArticle

(+)-Usnic Acid Induces ROS-dependent Apoptosis via Inhibition of Mitochondria Respiratory Chain Complexes and Nrf2 Expression in Lung Squamous Cell Carcinoma

by Wanchen Qi 1,2,3,4, Changpeng Lu 1,2,3,4, Huiliang Huang 1,2,3,4, Weinan Zhang 1,2,3,4, Shaofei Song 1 and Bing Liu 1,2,3,4,*
1
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
2
Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China
3
Key Laboratory of New Drug Discovery and Evaluation of ordinary universities of Guangdong province, Guangdong Pharmaceutical University, Guangzhou 510006, China
4
Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 876; https://doi.org/10.3390/ijms21030876
Received: 1 January 2020 / Revised: 24 January 2020 / Accepted: 27 January 2020 / Published: 29 January 2020
(This article belongs to the Section Molecular Oncology)
Lung squamous cell carcinoma (LUSC) has a poor prognosis, in part due to poor therapeutic response and limited therapeutic alternatives. Lichens are symbiotic organisms, producing a variety of substances with multiple biological activities. (+)-Usnic acid, an important biologically active metabolite of lichens, has been shown to have high anti-cancer activity at low doses. However, there have been no reports regarding the effect of (+)-usnic acid on LUSC cells. This study found that (+)-usnic acid reduced viability and induced apoptosis in LUSC cells by reactive oxygen species (ROS) accumulation. (+)-Usnic acid induced mitochondria-derived ROS production via inhibition of complex I and complex III of the mitochondrial respiratory chain (MRC). Interestingly, the elimination of mitochondrial ROS by Mito-TEMPOL only partially reversed the effect of (+)-usnic acid on cellular ROS production. Further study showed that (+)-usnic acid also induced ROS production via reducing Nrf2 stability through disruption of the PI3K/Akt pathway. The in vitro and in vivo xenograft studies showed that combined treatment of (+)-usnic acid and paclitaxel synergistically suppressed LUSC cells. In conclusion, this study indicates that (+)-usnic acid induces apoptosis of LUSC cells through ROS accumulation, probably via disrupting the mitochondrial respiratory chain (MRC) and the PI3K/Akt/Nrf2 pathway. Therefore, although clinical use of (+)-usnic acid will be limited due to toxicity issues, derivatives thereof may turn out as promising anticancer candidates for adjuvant treatment of LUSC. View Full-Text
Keywords: (+)-usnic acid; lung squamous cell carcinoma; reactive oxygen species (ROS); paclitaxel (+)-usnic acid; lung squamous cell carcinoma; reactive oxygen species (ROS); paclitaxel
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Qi, W.; Lu, C.; Huang, H.; Zhang, W.; Song, S.; Liu, B. (+)-Usnic Acid Induces ROS-dependent Apoptosis via Inhibition of Mitochondria Respiratory Chain Complexes and Nrf2 Expression in Lung Squamous Cell Carcinoma. Int. J. Mol. Sci. 2020, 21, 876.

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