Stabilization of VEGF G-quadruplex and inhibition of angiogenesis by quindoline derivatives

• Published in: Biochimica et biophysica acta Vol. 1840; no. 9; pp. 2970 - 2977
• Main Authors: Wu, Yue, Zan, Li-Peng, Wang, Xiao-Dong, Lu, Yu-Jing, Ou, Tian-Miao, Lin, Jing, Huang, Zhi-Shu, Gu, Lian-Quan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2014
• Subjects: Alkaloids - chemistry; Alkaloids - pharmacokinetics; Alkaloids - pharmacology; Angiogenesis; Animals; Anti-tumor; antineoplastic activity; carcinogenesis; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; cell proliferation; Cell Proliferation - drug effects; Chick Embryo; chickens; chicks; chorioallantoic membrane; Circular Dichroism; circular dichroism spectroscopy; CpG Islands; cytokines; DNA; embryogenesis; enzyme-linked immunosorbent assay; G-quadruplex; genes; Humans; Indoles - chemistry; Indoles - pharmacokinetics; Indoles - pharmacology; Ligands; luciferase; neoplasm cells; neoplasms; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; promoter regions; Promoter Regions, Genetic; Quindoline derivative; Quinolines - chemistry; Quinolines - pharmacokinetics; Quinolines - pharmacology; reverse transcriptase polymerase chain reaction; RNA; survival rate; transcription (genetics); Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; vascular endothelial growth factors; VEGF; Quindoline derivative; Angiogenesis; Anti-tumor; VEGF; G-quadruplex
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.06.002

Angiogenesis is thought to be important in tumorigenesis and tumor progress. Vascular endothelial growth factor (VEGF) is a pluripotent cytokine and angiogenic growth factor that plays crucial roles in embryonic development and tumor progression. In many types of cancer, VEGF is overexpressed and is generally associated with tumor progression and survival rate. The polypurine/polypyrimidine sequence located upstream of the promoter region in the human VEGF gene can form specific parallel G-quadruplex structures, raising the possibility for transcriptional control of VEGF through G-quadruplex ligands. PCR stop assay, circular dichroism (CD) spectra, RNA extraction and RT-PCR, enzyme-linked immunosorbent assay (ELISA), luciferase Assays, cell scrape test, xCELLigence real-time cell analysis (RTCA), and chick embryo chorioallantoic membrane (CAM) assay. We found that quindoline derivatives can interact with the G-rich DNA sequences of the VEGF promoter to stabilize this G-quadruplex and suppress the transcription and expression of the VEGF protein. We also demonstrated that these derivatives exhibit potential anti-angiogenic activity in chick embryos and antitumor activity, including the inhibition of cell proliferation and migration. Our new findings have significances not only for understanding the mechanism of the G-quadruplex ligands mediating the VEGF transcription inhibition, but also for exploring a new anti-tumor strategy to blocking the transcription of VEGF to inhibit the angiogenesis in cancer cells. •Inhibitory activity of quindoline derivative on angiogenesis is revealed.•Effects of quindoline derivative on VEGF are revealed.•The role of G-quadruplex in VEGF promoter on the transcription is illustrated.•Quindoline derivative is involved in the regulation of G-quadruplex on VEGF transcription.