title: Potentiation of anti-angiogenic activity of heparin by blocking the ATIII-interacting pentasaccharide unit and increasing net anionic charge.
abstract: Heparin, a potent anticoagulant used for the prevention of venous thromboembolism, has been recognized as a tumor angiogenesis inhibitor. Its limitation in clinical application for cancer therapy, however, arises from its strong anticoagulant activity, which causes associated adverse effects. In this study, we show the structural correlation of LHT7, a previously developed heparin-based angiogenesis inhibitor, with its influence on VEGF blockade and its decreased anticoagulant activity. LHT7 was characterized as having average seven molecules of sodium taurocholates conjugated to one molecule of low-molecular-weight heparin (LMWH). This study showed that the conjugation of sodium taurocholates selectively blocked interaction with antithrombin III (ATIII) while enhancing the binding with VEGF. This resulted in LHT7 to have negligible anticoagulant activity but potent anti-angiogenic activity. Following up on this finding, we showed that the bidirectional effect of sodium taurocholate conjugation was due to its unique structure, that is, the sterane core hindering the ATIII-binding pentasaccharide unit of LMWH with its bulky and rigid structural characteristics while the terminal sulfate group interacts with VEGF to produce stronger binding. In addition, we showed that LHT7 was localized in the tumor, especially on the endothelial cells. One explanation for this might be that LHT7 was delivered to the tumor via platelets.
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.forename: Myungjin
authors.initials: M
authors.lastname: Lee
authors.forename: Sang Mun
authors.initials: SM
authors.lastname: Bae
authors.forename: Jooho
authors.initials: J
authors.lastname: Park
authors.forename: Ok Cheol
authors.initials: OC
authors.lastname: Jeon
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Lee
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Han Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Beom Suk
authors.initials: BS
authors.lastname: Lee
authors.forename: Rang-Woon
authors.initials: RW
authors.lastname: Park
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000838:Anions / Q000737:chemistry; D000925:Anticoagulants / Q000494:pharmacology*; D000990:Antithrombin III / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D019073:HT29 Cells; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009389:Neovascularization, Pathologic; D009844:Oligosaccharides / Q000037:antagonists & inhibitors / Q000737:chemistry; D013656:Taurocholic Acid / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D000838:Anions; D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D009844:Oligosaccharides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013656:Taurocholic Acid; D000990:Antithrombin III