title: An apoptosis-homing peptide-conjugated low molecular weight heparin-taurocholate conjugate with antitumor properties.
abstract: Various angiogenesis inhibitors and apoptosis-targeting agents have been therapeutically applied in preclinical cancer models, some of which have been tested in clinical trials. In a previous study, we demonstrated that LHT7, a low molecular weight heparin (LMWH)-taurocholate conjugate, has strong antiangiogenic and tumor-suppressive activity and diminished anticoagulant properties. In this study, we developed LHT7-ApoPep-1, an apoptosis-homing peptide-conjugated variant of LHT7. LHT7-ApoPep-1 exhibited antiangiogenic activity in endothelial cell tube-formation assays and apoptotic cell-targeting ability in tumor cell binding assays; it also showed little toxicity toward healthy cells. Administration of LHT7-ApoPep-1 in mouse xenograft models of breast carcinoma delayed tumor growth compared to LHT7-only, and histological evaluations revealed decreased vessel formation and increased apoptotic area in tumor tissues. Moreover, an examination of LHT7-ApoPep-1-Cy7.5 localization within the body using in vivo live imaging showed accumulation at the tumor site of tumor-bearing mice, with a more prolonged circulation time and enhanced intensity compared to LHT7-Cy7.5. Inspection of the tumor microenvironment revealed that Cy5.5-labeled LHT7-ApoPep-1 was located on and near CD31-positive vessels in tumor tissue. We conclude that LHT7-ApoPep-1 has antiangiogenic and apoptosis-targeting properties and exerts antitumor effects by suppressing tumor vessel growth and homing to apoptotic cells within the tumor.
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Sang Mun
authors.initials: SM
authors.lastname: Bae
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Byung-Heon
authors.initials: BH
authors.lastname: Lee
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.forename: Rang-Woon
authors.initials: RW
authors.lastname: Park
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006495:Heparin, Low-Molecular-Weight; C580866:LHT7 compound; D010455:Peptides; D013656:Taurocholic Acid