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.
Highlights
Many cancers have common, overexpressed molecular elements associated with the diseased state and include several membrane proteins, such as cytokine/ chemokine receptors, receptor tyrosine kinases, and integrins [1]
To identify cyclic peptides that bind to the integrin αvβ3, an M13 phage peptide library was used with inserts coding cysteine-flanked random heptapeptide
We report here a novel cyclic nonapeptide, ALOS4, with potent anticancer activity against an aggressive melanoma model
Summary
Many cancers have common, overexpressed molecular elements associated with the diseased state and include several membrane proteins, such as cytokine/ chemokine receptors, receptor tyrosine kinases, and integrins [1]. Integrins are heterodimeric cell-surface glycoproteins that trigger a diversity of signaling pathways controlling cell adhesion, proliferation, survival, morphology, motility, cell cycle progression and cell differentiation [2, 3]. They are critical for angiogenesis [1], lymphangiogenesis [1], thrombocytosis [4, 5] and immune response [6,7,8] and are involved in various human pathologies including inflammation [9, 10], fibrosis [9], infectious diseases [11,12,13] and cancer [1]. Recent studies demonstrate that αvβ binds proteins that do not contain canonical RGD sequences [28]
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