Polyproline-type helical-structured low-molecular weight heparin (LMWH)-taurocholate conjugate as a new angiogenesis inhibitor

Esak Lee, Yoo Shin Kim, Sang Mun Bae, Sang Kyoon Kim, Shunji Jin, Seung Woo Chung, Myungjin Lee, Hyun Tae Moon, Ok Cheol Jeon, Rang Woon Park, In San Kim, Youngro Byun, Sang Yoon Kim

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Abstract

Although heparin can regulate angiogenesis, tumor growth and metastasis, its clinical application, as well as that of low-molecular heparin (LMWH), for treating cancer are limited because of heparin's anticoagulant activity and risk of hemorrhages. LMWH-taurocholate conjugates (LHT7), which have low anticoagulant activity, were synthesized. The structural property of LHT was evaluated by circular dichroism and the binding affinity of LHT7 to vascular endothelial growth factor 165 (VEGF165) was measured by isothermal titration calorimetry. The inhibitory effect of LHT7 on VEGF-mediated KDR (VEGF-receptor 2) phosphorylation in Human umbilical vein endothelial cells was evaluated. The VEGF165 dependent Matrigel plug assay was performed to verify the antiangiogenic potential of LHT7 on a VEGF165 inhibitor. Finally, tumor growth inhibition effects of LHT7 on SCC7 and the survival rate of animal models were investigated. Moreover, MDA-MB231 xenograft mouse model was additionally used to confirm the therapeutic effect of LHT7 on human breast cancer cell line. As a result, LHT7 which has 12.7% of anticoagulant activity of the original LMWH showed a peculiar polyproline-type helical structure. LHT7 binds to VEGF strongly and inhibits VEGF dependent KDR phosphorylation. The results of Matrigel plug assay proved LHT7 as a strong antiangiogenic agent inhibiting VEGF165. Remarkably, LHT7 showed a significant tumor growth inhibition potential on SCC7 with an increased survival rate. LHT7 also delayed tumor growth in MDA-MB231 human breast cancer cell lines.

Original languageEnglish
Pages (from-to)2755-2765
Number of pages11
JournalInternational Journal of Cancer
Volume124
Issue number12
DOIs
Publication statusPublished - 2009 Jun 15

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Keywords

  • Angiogenesis
  • LMWH-taurocholate conjugate
  • Polyproline-type helical structure
  • Vascular endothelial growth factors 165 (VEGF165)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lee, E., Kim, Y. S., Bae, S. M., Kim, S. K., Jin, S., Chung, S. W., Lee, M., Moon, H. T., Jeon, O. C., Park, R. W., Kim, I. S., Byun, Y., & Kim, S. Y. (2009). Polyproline-type helical-structured low-molecular weight heparin (LMWH)-taurocholate conjugate as a new angiogenesis inhibitor. International Journal of Cancer, 124(12), 2755-2765. https://doi.org/10.1002/ijc.24239