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Antiangiogenic Effect of Bile Acid Acylated Heparin Derivative

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Abstract

Purpose

Chemically modified heparin–DOCA was prepared and found to have markedly lower anticoagulant activity than heparin. In the present study, we elucidated the antiangiogenic and antitumoral activities of heparin–DOCA derivative.

Methods

To evaluate the antiangiogenic and antitumoral effects of heparin–DOCA, capillary-like tube formation assay, Matrigel plug assay in vivo, western blotting for FGFR phosphorylation, ERK and p38 MAPK activities, tumor growth of SCC in vivo and immunostaining of blood vessels in tumor tissues were performed.

Results

Heparin–DOCA inhibited capillary-like tubular structures of endothelial cells and bFGF-induced neovascularizations in Matrigel plug assays. Signaling experiments showed that heparin–DOCA significantly inhibited angiogenesis by suppressing the phosphorylation of FGFR and its downstream signal pathways (ERK and p38 MAPK activities). The antiangiogenic activity of this heparin derivative was found to be closely associated with antitumoral activity in a mouse model. In addition, histological evaluations supported the inhibitory effect of heparin–DOCA on blood vessel formation in tumor tissues.

Conclusion

Heparin–DOCA derivative exerted a significant antitumoral effect by inhibiting angiogenesis resulting from the disruption of FGF/FGFR and its downstream signal pathways, and could be applied to treat various angiogenic diseases.

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Abbreviations

aPTT:

activated partial thromboplastin time

bFGF:

basic fibroblast growth factor

DOCA-NH2 :

N-deoxycholylethylenediamine

ECM:

extracellular matrix

ERK:

extracellular signal-regulated kinase

FGFR:

fibroblast growth factor receptor

HSPGs:

heparan sulfate proteoglycans

HUVECs:

human umbilical vein endothelial cells

MAPK:

mitogen-activated protein kinase

SCC:

squamous cell carcinoma

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Acknowledgment

This work was supported by the Next generation New Technology Development Program of the Korean Ministry of Commerce, Industry, and Energy (Grant No. #10011353).

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Authors and Affiliations

  1. College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, South Korea

    Kyeongsoon Park, Gee Young Lee & Youngro Byun

  2. Department of Biochemistry, School of Medicine, Kyungpook National University, 101 Dongin-dong, Jung-gu, Daegu, 700-422, South Korea

    Yoo-Shin Kim, Ju-Ock Nam, Rang-Woon Park & In-San Kim

  3. Department of Otolaryngology, College of Medicine, Kangwon National University, 191-2 Hyoja-dong, Chunchon, 200-701, South Korea

    Seok Ki Lee

  4. Department of Otolaryngology, College of Medicine, University of Ulsan, 388-1 Pungnap-dong, Songpa-gu, Seoul, 138-736, South Korea

    Sang Yoon Kim

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  1. Kyeongsoon Park
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Correspondence to Youngro Byun.

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Park, K., Kim, YS., Lee, G.Y. et al. Antiangiogenic Effect of Bile Acid Acylated Heparin Derivative. Pharm Res 24, 176–185 (2007). https://doi.org/10.1007/s11095-006-9139-6

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  • DOI: https://doi.org/10.1007/s11095-006-9139-6

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