Alantolactone enhances gemcitabine sensitivity of lung cancer cells through the reactive oxygen species-mediated endoplasmic reticulum stress and Akt/GSK3β pathway

Lung cancer is one of the leading causes of cancer-associated mortality in China and globally. Gemcitabine (GEM), as a first-line therapeutic drug, has been used to treat lung cancer, but GEM resistance poses a major limitation on the efficacy of GEM chemotherapy. Alantolactone (ALT), a sesquiterpene lactone compound isolated from Inula helenium, has been identified to exert anticancer activity in various types of cancer, including breast, pancreatic, lung squamous and colorectal cancer. However, the underlying mechanisms of the anticancer activity of ALT in lung cancer remain to be fully elucidated. The present study aimed to determine whether ALT enhances the anticancer efficacy of GEM in lung cancer cells and investigated the underlying mechanisms. The cell viability was assessed with a Cell Counting Kit-8 assay. The cell cycle, apoptosis and the level of reactive oxygen species (ROS) were assessed by flow cytometry, and the expression of cell cycle-associated and apoptosis-associated proteins were determined by western blot analysis. The results demonstrated that ALT inhibited cell growth and induced S-phase arrest and cell apoptosis in A549 and NCI-H520 cells. Furthermore, ALT increased the level of ROS, inhibited the Akt/glycogen synthase kinase (GSK)3β pathway and induced endoplasmic reticulum (ER) stress in A549 and NCI-H520 cells. Additionally, ALT treatment sensitized lung cancer cells to GEM. Analysis of the molecular mechanisms further revealed that ALT enhanced the anticancer effects of GEM via ROS-mediated activation of the Akt/GSK3β and ER stress pathways. In conclusion, combined treatment with ALT and GEM may have potential as a clinical strategy for lung cancer treatment.