CIGB-300, a proapoptotic peptide, inhibits angiogenesis in vitro and in vivo

• Published in: Experimental cell research 2011-07, Vol.317 (12), p.1677-1688
• Main Authors: Farina, Hernán G., Benavent Acero, Fernando, Perera, Yasser, Rodríguez, Arielis, Perea, Silvio E., Castro, Boris Acevedo, Gomez, Roberto, Alonso, Daniel F., Gomez, Daniel E.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Apoptosis - drug effects; Biomarkers - metabolism; Blotting, Western; CAM; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane - drug effects; Chorioallantoic Membrane - metabolism; CIGB-300; CK2; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Expression Profiling; Humans; HUVEC; In Vitro Techniques; Neovascularization, Pathologic - prevention & control; Oligonucleotide Array Sequence Analysis; Peptides; Peptides, Cyclic - pharmacology; Umbilical Veins - cytology; Umbilical Veins - drug effects; Umbilical Veins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2011.04.011

We have previously demonstrated that a proapoptotic cyclic peptide CIGB-300, formerly known as P15-Tat delivered into the cells by the cell-penetrating peptide Tat, was able to abrogate the CK2-mediated phosphorylation and induce tumor regression when injected directly into solid tumors in mice or by systemic administration. In this work, we studied the role of CIGB-300 on the main events that take place in angiogenesis. At non-cytotoxic doses, CIGB-300 was able to inhibit adhesion, migration, and tubular network formation induced by human umbilical vein endothelial cells (HUVEC) growing upon Matrigel in vitro. Likewise, we evaluated the cellular penetration and localization into the HUVEC cells of CIGB-300. Our results confirmed a quick cellular penetration and a cytoplasmic accumulation in the early minutes of incubation and a translocation into the nuclei beginning at 12 h of treatment, with a strong presence in the perinuclear area. A microarray analysis was used to determine the genes affected by the treatment. We observed that CIGB-300 significantly decreased four genes strongly associated with tubulogenesis, growth, and differentiation of endothelial cells. The CIGB-300 was tested in vivo on chicken embryo chorioallantoic membranes (CAM), and a large number of newly formed blood vessels were significantly regressed. The results suggested that CIGB-300 has a potential as an antiangiogenic treatment. The mechanism of action may be associated with partial inhibition of VEGF and Notch pathways.