title: LHT7, a chemically modified heparin, inhibits multiple stages of angiogenesis by blocking VEGF, FGF2 and PDGF-B signaling pathways.
abstract: Despite the therapeutic benefits of the angiogenesis inhibitors shown in the clinics, they have encountered an unexpected limitation by the occurrence of acquired resistance. Although the mechanism of the resistance is not clear so far, the upregulation of alternative angiogenic pathways and stabilization of endothelium by mural cells were reported to be responsible. Therefore, blocking multiple angiogenic pathways that are crucial in tumor angiogenesis has been highlighted to overcome such limitations. To develop an angiogenesis inhibitor that could block multiple angiogenic factors, heparin is an excellent lead compound since wide array of angiogenic factors are heparin-binding proteins. In previous study, we reported a heparin-derived angiogenesis inhibitor, LHT7, as a potent angiogenesis inhibitor and showed that it blocked VEGF signaling pathway. Here we show that LHT7 could block the fibroblast growth factor 2 (FGF2) and platelet-derived growth factor B (PDGF-B) in addition to VEGF. Simultaneous blockade of these angiogenic factors resulted in inhibition of multiple stages of the angiogenic process, including initial angiogenic response to maturation of the endothelium by pericyte coverage in vitro. In addition, the treatment of LHT7 in vivo did not show any sign of vascular normalization and directly led to decreased blood perfusion throughout the tumor. Our findings show that LHT7 could effectively inhibit tumor angiogenesis by blocking multiple stages of the angiogenesis, and could potentially be used to overcome the resistance.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 700-422, South Korea.
authors.forename: Sang Mun
authors.initials: SM
authors.lastname: Bae
authors.affiliation: Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Cheongwon, Chungbuk 363-883, South Korea; Department of Radiology, Research Institute of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea.
authors.forename: Chang Kyung
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Cheongwon, Chungbuk 363-883, South Korea; Department of Radiology, Research Institute of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea.
authors.forename: Jeong Kon
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 700-422, South Korea; Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea; Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul 151-742, South Korea. Electronic address: yrbyun@snu.ac.kr.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D003287:Contrast Media; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D007797:Laminin / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism*; D020286:Pericytes / Q000166:cytology / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D004338:Drug Combinations; D006495:Heparin, Low-Molecular-Weight; C580866:LHT7 compound; D007797:Laminin; D011509:Proteoglycans; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D013656:Taurocholic Acid; D003094:Collagen
keywords: Angiogenesis; FGF2; Heparin; PDGF-B; VEGF