Shikonin sensitizes wild-type EGFR NSCLC cells to erlotinib and gefitinib therapy

As patients with non-small cell lung cancer (NSCLC) and wild-type epidermal growth factor receptor (EGFR) are resistant to treatment with erlotinib or gefitinib, potential chemosensitizers are required to potentiate wild-type EGFR NSCLC cells to erlotinib/gefitinib treatment. The present study reported that shikonin could sensitize the anticancer activity of erlotinib/gefitinib in wild-type EGFR NSCLC cells. Furthermore, shikonin could potentiate mitochondrial-mediated apoptosis induced by erlotinib/gefitinib in wild-type EGFR NSCLC cells. In addition, the present study demonstrated that shikonin could induce apoptosis by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, and that erlotinib/gefitinib may also induce ER stress in wild-type EGFR NSCLC cells; however, shikonin plus erlotinib/gefitinib was more effective in activating ER stress than either agent alone. This indicated that ROS-mediated ER stress may be associated with enhanced mitochondrial apoptosis induced by shikonin plus erlotinib/gefitinib. In addition, shikonin may promote the transition of cytoprotective ER stress-inducing EGFR-tyrosine kinase inhibitor tolerance to apoptosis-promoting ER stress. Furthermore, shikonin may enhance the anti-NSCLC activity of erlotinib/gefitinib in vivo. The data of the present study indicated that shikonin may be a potential sensitizer to enhance the anti-cancer efficacy of erlotinib/gefitinib in wild-type EGFR NSCLC cells resistant to erlotinib/gefitinib treatment.