Regulation of VEGF gene expression by bisacridine derivative through promoter i-motif for cancer treatment

Vascular endothelial growth factor (VEGF) is overexpressed in most malignant tumors, which has important impact on tumor angiogenesis and development. Its gene promoter i-motif structure formed by C-rich sequence can regulate gene expression, which is a promising new target for anti-tumor therapy. We screened various compounds and studied their effects on VEGF through extensive experiments, including SPR, MST, TO displacement, FRET, CD, ESI-MS, NMR, MTT, clone formation, qPCR, Western blot, dual-luciferase reporter assay, immunofluorescence, cell scrape, apoptosis, transwell assay, and animal model. After extensive screening, bisacridine derivative B09 was found to have selective binding and stabilization to VEGF promoter i-motif, which could down-regulate VEGF gene expression. B09 showed potent inhibition on MCF-7 and HGC-27 cell proliferation and metastasis. B09 significantly inhibited tumor growth in xenograft mice model with HGC-27 cells, showing decreased VEGF expression analyzed through immunohistochemistry. B09 could specifically regulate VEGF gene expression, possibly through interacting with promoter i-motif structure. As a lead compound, B09 could be further developed for innovative anti-cancer agent targeting VEGF. •VEGF is a significant anti-tumor target overexpressed in various types of cancers.•Bisacridine derivative B09 specifically bound to and stabilized VEGF promoter i-motif.•B09 selectively down-regulated VEGF gene expression through promoter i-motif.•B09 showed strong inhibition on MCF-7 and HGC-27 cells proliferation and migration.•B09 had potent anti-cancer activity in HGC-27 xenograft mice model.