title: Polyproline-type helical-structured low-molecular weight heparin (LMWH)-taurocholate conjugate as a new angiogenesis inhibitor.
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 (VEGF(165)) 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 VEGF(165) dependent Matrigel plug assay was performed to verify the antiangiogenic potential of LHT7 on a VEGF(165) 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 VEGF(165). 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.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Esak
authors.initials: E
authors.lastname: Lee
authors.forename: Yoo-Shin
authors.initials: YS
authors.lastname: Kim
authors.forename: Sang Mun
authors.initials: SM
authors.lastname: Bae
authors.forename: Sang Kyoon
authors.initials: SK
authors.lastname: Kim
authors.forename: Shunji
authors.initials: S
authors.lastname: Jin
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.forename: Myungjin
authors.initials: M
authors.lastname: Lee
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Moon
authors.forename: Ok-Cheol
authors.initials: OC
authors.lastname: Jeon
authors.forename: Rang Woon
authors.initials: RW
authors.lastname: Park
authors.forename: In San
authors.initials: IS
authors.lastname: Kim
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002942:Circular Dichroism; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007797:Laminin; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry*; D010766:Phosphorylation; D011509:Proteoglycans; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D006495:Heparin, Low-Molecular-Weight; C580866:LHT7 compound; D007797:Laminin; D010455:Peptides; D011509:Proteoglycans; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; C011083:polyproline; D013656:Taurocholic Acid; D006493:Heparin; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2