title: Src inhibition potentiates antitumoral effect of paclitaxel by blocking tumor-induced angiogenesis.
abstract: The protein kinase Src is frequently over-activated in advanced cancers where it modulates the signaling transduction cascade of several growth factors. The feasibility of combination treatment of Src inhibitors with chemotherapy is currently under investigation. We evaluated the anti-tumoral effect of paclitaxel (PTX) in combination with S13, a tyrosine kinase inhibitor with a prevalent specificity for Src, in a hormone-insensible prostate cancer (PCa) cell model. In vivo, combination treatment with PTX and S13 reduced dramatically PCa tumor growth with a relevant difference in the density of new blood vessels with respect to control and single treatments. This reduction was determined by a concomitant impairment of endothelial cell migration and of VEGF release by cancer cells. In fact, S13, when used alone, was sufficient to reduce tubule formation in vivo, and to inhibit VEGFR2 activation and FAK expression in endothelial cells. In addition, the combination treatment determined a significant reduction in ROS production and HIF-1 stabilization in PCa cells respect to single treatments with S13 or PTX. In conclusion, Src-inhibition could be an effective therapeutic strategy aimed at supporting the anti-angiogenic action of PTX in aggressive PCa.
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, University of L׳Aquila, via Vetoio Coppito, 67100 L׳Aquila, Italy. Electronic address: simona.dellemonache@univaq.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Delle Monache
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, University of L׳Aquila, via Vetoio Coppito, 67100 L׳Aquila, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sanità
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, University of L׳Aquila, via Vetoio Coppito, 67100 L׳Aquila, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Calgani
authors.affiliation: Dipartimento di Farmacia, University of Genova, viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, University of via A. Moro, snc, 53100, Siena, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Botta
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, University of L׳Aquila, via Vetoio Coppito, 67100 L׳Aquila, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D017239:Paclitaxel
keywords: Angiogenesis; Chemotherapy; Prostate cancer; Reactive oxygen species.; Src; Taxanes