Naphthoquinone Derivatives from the Endophytic Fungus Fusarium solani Induce Pancreatic Cancer Cells Apoptosis via Targeting EGFR-Mediated PI3K/Akt Pathway

Seven
new polyketide compounds, four naphthoquinone derivatives,
neofusarubins A–D (1, 3, 5, and 18) and three graminin-like compounds, fusofuranones
A–C (19–21), together with
14 known naphthoquinone derivatives, were isolated from the solid
fermentation of Fusarium solani, an
endophytic fungus obtained from medicinal plant as tea, Camellia chrysantha. The structures of new compounds
were elucidated based on chemical evidence and spectral data analysis
(1D and 2D-NMR, HR-ESI-MS, ECD, SC-XRD). Among the isolated compounds
tested, 2-acetonyl-3-methyl-5-hydroxy-7-methoxy-naphthazarin (11) exhibited the most potent inhibitory activity against
pancreatic cancer in PANC-1, MiaPaCa-2, and BxPC-3 cells. Network
pharmacology analysis revealed that compound 11 inhibited
cell proliferation and promotion of apoptosis by targeting epidermal
growth factor receptor (EGFR), which were confirmed by cellular thermal
shift assay (CETSA), microscale thermophoresis (MST) and EGFR stably
knockdown cells model assay, respectively. In addition, molecular
mechanism studies in vitro showed that 11 could suppress the growth of pancreatic cancer cells by targeting
EGFR and effectively inhibit downstream PI3K/Akt signaling pathway.
Collectively, these findings provide a new EGFR targeting natural
product for the treatment of pancreatic cancer.