Griffithazanone A, a sensitizer of EGFR-targeted drug in for non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which accounts for up to 85 % of lung cancer cases, significantly impacts the health of individuals worldwide. While targeted therapy has played a crucial role, the emergence of EGFR resistance and adverse reactions has made it imperative to explore new medications. Natural products derived from plants became an important source of anti-tumor drugs. In this study, nine known compounds, including seven alkaloids (-) and two styryllactones ( and ) were isolated from twigs and leaves of Their structures were elucidated by their NMR spectroscopic data. Among them, griffithazanone A () showed the strongest inhibitory activity with the IC value of 6.775 μM. Our findings revealed that griffithazanone A treatment induced cytotoxicity, apoptosis, and ROS generation in A549 cells in a dose-dependent manner. It regulates the expression of apoptosis-related proteins Bax, Bcl-2, and cleaved-caspase3 both and . Further investigation demonstrated that griffithazanone A regulated the proteins involved in the ASK1/JNK/p38 and BAD/Bcl-2 pathways in A549 cells by targeting PIM1. Moreover, griffithazanone A treatment enhanced the efficacy of gefitinib and osimertinib and reversed osimertinib resistance. Overall, our study highlights the potential of griffithazanone A in inhibiting the progression of NSCLC by targeting PIM1 and reversing resistance to EGFR targeted drugs.