Schizandrin A enhances the efficacy of gefitinib by suppressing IKKβ/NF-κB signaling in non-small cell lung cancer.

The emergence of resistance to EGF receptor (EGFR) inhibitor therapy is a significant challenge for patients with non-small cell lung cancer (NSCLC). During the past few years, a correlation between EGFR TKIs resistance and dysregulation of IKKβ/NF-κB signaling has been increasingly suggested. However, few studies have focused on the effects of combining IKK/NF-κB and EGFR inhibitors to overcome EGFR TKIs resistance. In this study, we discovered that Schizandrin A (Sch A), a lignin compound isolated from Schisandra chinesnesis, could synergize with the EGFR receptor inhibitor Gefitinib to inhibit cell growth, induce cell cycle arrest and apoptosis of HCC827/GR cells. Sch A effectively suppressed the phosphorylation of IKKβ and IκBα, as well as the nuclear translocation of NF-κB p65, and showed high and selective affinity for IKKβ in surface plasmon resonance (SPR) experiments, indicating that Sch A was a selective IKKβ inhibitor. Molecular modeling between IKKβ and Sch A suggested that Sch A formed key hydrophobic interactions with IKKβ, which may contribute to its potent IKKβ inhibitory effect. These findings suggest a novel approach to improve poor clinical outcomes in EGFR TKIs therapy, by combining it with Sch A.