Fuzheng Kang-Ai decoction increases the sensitivity of Gefitinib via inducing Non-Small Cell Lung Cancer ferroptosis through AMPK/SLC7A11 pathway

Abstract

Abstract Background: Fuzheng Kang-Ai decoction (FZKA), which consists of twelve Chinese herbal medicines (CHM), has been extensively used in the treatment of Non-Small Cell Lung Cancer (NSCLC) patients. It was reported in our preceding study that the progression-free survival (PFS) could be prolonged and the toxic effect was reduced after the combination of FZKA and Gefitinib (GFTN) comparing to GFTN alone. Recent studies have shown that FZKA could promote ferroptosis in NSCLC cells. Hence, we assumed that FZKA might strengthen the effect of GFTN by regulating cell ferroptosis in NSCLC. Results: First of all, according to our results, FZKA increased the inhibition effect of NSCLC by GFTN in vitro. Next, we found that FZKA increased the sensitivity of GFTN on cell ferroptosis by testing lipid peroxidation and intracellular-free iron. Interestingly, the effect of FZKA on increasing sensitivity of GFTN in NSCLC cells could be reversed by blocking ferroptosis. Additionally, the results demonstrated that the expression of AMPKα was increased and SLC7A11 reduced in the combined treatment group, at both mRNA and protein levels. Notably, the inhibition of AMPKα reversed the effect of FZKA on increasing GFTN sensitivity. Finally, in vivoexperiments validated that FZKA strengthened the effect of GFTN by inducing NSCLC cell ferroptosis. Conclusions: Based on our findings, we conclude that FZKA increases the sensitivity of GFTN via inducing NSCLC ferroptosis through AMPK/SLC7A11 pathway, providing the solid evidences to the treatment of FZKA together with GFTN in NSCLC patients.