(+)-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 Jan 29;21(3):876. doi: 10.3390/ijms21030876.


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.

Keywords: (+)-usnic acid; lung squamous cell carcinoma; paclitaxel; reactive oxygen species (ROS).

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Benzofurans / therapeutic use
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Electron Transport Chain Complex Proteins / antagonists & inhibitors
  • Electron Transport Chain Complex Proteins / metabolism*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / metabolism*
  • Paclitaxel / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects
  • Transplantation, Heterologous


  • Antineoplastic Agents, Phytogenic
  • Benzofurans
  • Electron Transport Chain Complex Proteins
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • usnic acid
  • Proto-Oncogene Proteins c-akt
  • Paclitaxel