Novel synthetic cyclic integrin αvβ3 binding peptide ALOS4: antitumor activity in mouse melanoma models
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Shiri Yacobovich1, Lena Tuchinsky1, Michael Kirby1, Tetiana Kardash1, Oryan Agranyoni1, Elimelech Nesher1,2, Boris Redko3, Gary Gellerman3, Dror Tobi1, Katerina Gurova2, Igor Koman1, Osnat Ashur Fabian4, Albert Pinhasov1
1Department of Molecular Biology, Ariel University, Ariel, Israel
2Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA
3Department of Chemical Sciences, Ariel University, Ariel, Israel
4Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Albert Pinhasov, email: [email protected]
Keywords: cancer, cyclic peptide, integrin, ALOS4, melanoma
Received: March 13, 2016 Accepted: July 27, 2016 Published: August 18, 2016
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.
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