Targeting thioredoxin reductase 1 by Andrographolide contributes to inducing ROS-mediated apoptosis in human NSCLC cells

Non-small cell lung cancer (NSCLC) is the most commonly diagnosed malignancy, causing a large number of deaths annually. Finding new drug candidates for treating advanced lung cancer is an urgent need. Andrographolide (Andro), a diterpenoid lactone, derived from Andrographis paniculata Nees and used in traditional Chinese medicine. Andro exhibits potential anticancer activity in multiple types of human cancers. In the present study, we focused on exploring the underlying mechanisms of Andro treatment in NSCLC. The results showed that Andro targets and inhibits the thioredoxin reductase 1 (TrxR1), which caused reactive oxygen species (ROS) production and induce ROS-dependent endoplasmic reticulum (ER) stress and apoptosis in human NSCLC cells. Blockage of ROS generation totally reversed Andro-induced ER stress and apoptosis effects. Critically, TrxR1 knockdown sensitized H460 cancer cells to Andro treatment, whereas TrxR1 overexpression conferred resistance to Andro-induced cytotoxicity in these cells. Treatment with Andro in mice bearing NSCLC xenografts significantly suppressed tumor progression, which was closely linked to TrxR1 activity inhibition and subsequent ROS accumulation. Notably, clinical data revealed that elevated TrxR1 expression levels in lung cancer patients were positively associated with poor prognosis. Our study reveals the molecular mechanism underlying Andro's antitumor effects in NSCLC and highlights TrxR1 as a promising therapeutic target for NSCLC treatment.