LHT7, a chemically modified heparin, inhibits multiple stages of angiogenesis by blocking VEGF, FGF2 and PDGF-B signaling pathways

Seung Woo Chung, Sang Mun Bae, Myungjin Lee, Taslim A. Al-Hilal, Chang Kyung Lee, Jeong Kon Kim, In-San Kim, Sang Yoon Kim, Youngro Byun

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 invitro. In addition, the treatment of LHT7 invivo 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.

Original languageEnglish
Pages (from-to)271-278
Number of pages8
JournalBiomaterials
Volume37
DOIs
Publication statusPublished - 2015 Jan 1
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-sis
Angiogenesis Inhibitors
Fibroblast Growth Factor 2
Fibroblasts
Platelets
Vascular Endothelial Growth Factor A
Heparin
Tumors
Angiogenesis Inducing Agents
Lead compounds
Endothelium
Neoplasms
Pericytes
Blood
Stabilization
Blood Vessels
Up-Regulation
Perfusion
Intercellular Signaling Peptides and Proteins

Keywords

  • Angiogenesis
  • FGF2
  • Heparin
  • PDGF-B
  • VEGF

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

LHT7, a chemically modified heparin, inhibits multiple stages of angiogenesis by blocking VEGF, FGF2 and PDGF-B signaling pathways. / Chung, Seung Woo; Bae, Sang Mun; Lee, Myungjin; Al-Hilal, Taslim A.; Lee, Chang Kyung; Kim, Jeong Kon; Kim, In-San; Kim, Sang Yoon; Byun, Youngro.

In: Biomaterials, Vol. 37, 01.01.2015, p. 271-278.

Research output: Contribution to journalArticle

Chung, Seung Woo ; Bae, Sang Mun ; Lee, Myungjin ; Al-Hilal, Taslim A. ; Lee, Chang Kyung ; Kim, Jeong Kon ; Kim, In-San ; Kim, Sang Yoon ; Byun, Youngro. / LHT7, a chemically modified heparin, inhibits multiple stages of angiogenesis by blocking VEGF, FGF2 and PDGF-B signaling pathways. In: Biomaterials. 2015 ; Vol. 37. pp. 271-278.
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