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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 7; p. 130631
• Main Authors: Wang, Jing, Wang, Siyi, Zhang, Jiahui, Ji, Dongsheng, Huang, Zhi-Shu, Li, Ding
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2024
• Subjects: Acridine; Acridines - chemistry; Acridines - pharmacology; angiogenesis; animal models; Animals; antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; bioluminescence assay; Cancer; cancer therapy; Cell Line, Tumor; cell proliferation; Cell Proliferation - drug effects; Female; fluorescent antibody technique; gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene regulation; genes; Humans; I-motif; immunohistochemistry; MCF-7 Cells; metastasis; Mice; Mice, Nude; neoplasms; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Promoter Regions, Genetic - drug effects; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; vascular endothelial growth factors; VEGF; Western blotting; Xenograft Model Antitumor Assays; xenotransplantation; PBS; Acridine; VEGF; Gene regulation; DAPI; MTT; I-motif; Fluc; KD; PI; Tm; FRET; Cancer
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130631

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.