title: Novel synthetic cyclic integrin αvβ3 binding peptide ALOS4: Antitumor activity in mouse melanoma models.
abstract: ALOS4, a unique synthetic cyclic peptide without resemblance to known integrin ligand sequences, was discovered through repeated biopanning with pIII phage expressing a disulfide-constrained nonapeptide library. Binding assays using a FITC-labeled analogue demonstrated selective binding to immobilized αvβ3 and a lack of significant binding to other common proteins, such as bovine serum albumin and collagen. In B16F10 cell cultures, ALOS4 treatment at 72 h inhibited cell migration (30%) and adhesion (up to 67%). Immunofluorescent imaging an ALOS4-FITC analogue with B16F10 cells demonstrated rapid cell surface binding, and uptake and localization in the cytoplasm. Daily injections of ALOS4 (0.1, 0.3 or 0.5 mg/kg i.p.) to mice inoculated with B16F10 mouse melanoma cells in two different cancer models, metastatic and subcutaneous tumor, resulted in reduction of lung tumor count (metastatic) and tumor mass (subcutaneous) and increased survival of animals monitored to 45 and 60 days, respectively. Examination of cellular activity indicated that ALOS4 produces inhibition of cell migration and adhesion in a concentration-dependent manner. Collectively, these results suggest that ALOS4 is a structurally-unique selective αvβ3 integrin ligand with potential anti-metastatic activity.
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Yacobovich
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Tuchinsky
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Kirby
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Tetiana
authors.initials: T
authors.lastname: Kardash
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Oryan
authors.initials: O
authors.lastname: Agranyoni
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.|Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Elimelech
authors.initials: E
authors.lastname: Nesher
authors.affiliation: Department of Chemical Sciences, Ariel University, Ariel, Israel.
authors.forename: Boris
authors.initials: B
authors.lastname: Redko
authors.affiliation: Department of Chemical Sciences, Ariel University, Ariel, Israel.
authors.forename: Gary
authors.initials: G
authors.lastname: Gellerman
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Tobi
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Gurova
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Igor
authors.initials: I
authors.lastname: Koman
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Ashur Fabian
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Albert
authors.initials: A
authors.lastname: Pinhasov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D039302:Integrin alphaVbeta3; D019151:Peptide Library; D010456:Peptides, Cyclic
keywords: ALOS4; cancer; cyclic peptide; integrin; melanoma