Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models
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Valeria Cicatiello1,2,*, Ivana Apicella1,*, Laura Tudisco1,*, Valeria Tarallo1, Luigi Formisano3, Annamaria Sandomenico4, Younghee Kim5, Ana Bastos-Carvalho5, Augusto Orlandi6, Jayakrishna Ambati5, Menotti Ruvo4, Roberto Bianco3, Sandro De Falco1,7
1Angiogenesis Lab, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” – CNR, Naples, Italy
2Bio-Ker, MultiMedica Group, Napoli, Italy
3Medical Oncology, Department of Clinic Medicine and Surgery, University of Naples “Federico II”, Italy
4Institute of Biostructures and Bioimaging – CNR and CIRPeB, University of Naples “Federico II”, Italy
5Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, KY, USA
6Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy
7IRCCS MultiMedica, Milan, Italy
*These authors have contributed equally to this work
Sandro De Falco, e-mail: [email protected]
Keywords: colorectal cancer, VEGFR1, angiogenesis, metastasis, choroid neovascularization
Received: January 21, 2015 Accepted: February 14, 2015 Published: March 25, 2015
To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.
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