期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/ijms21030876
关键词
(+)-usnic acid; lung squamous cell carcinoma; reactive oxygen species (ROS); paclitaxel
资金
- project of the new star of Zhujiang science and technology [201710010001]
- National Natural Science Foundation of China [81972821, 81672836]
- projects of Guangzhou key laboratory of construction and application of new drug screening model systems [201805010006]
- Key Laboratory of New Drug Discovery and Evaluation of ordinary universities of Guangdong province [2017KSYS002]
- Innovation Team Projects in Universities of Guangdong Province [2018KCXTD016]
- National Science and Technology Major Project [2017ZX09101001]
- Training Program of Innovation and Entrepreneurship for Undergraduates of Guangdong province [201910573001]
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.
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