14K Prolactin Derived 14-Mer Antiangiogenic Peptide Targets Bradykinin-/Nitric Oxide-cGMP-Dependent Angiogenesis

Abstract

VEGF-targeted antiangiogenic therapy for cancers has been principally used but also faced a limitation due to resistance and adverse effects in clinical application. This observation further endorses the need for novel anti-angiogenesis molecules and/or understanding of the mechanisms of tumor angiogenesis before clinical trial. In the present study, we investigated the antiangiogenic properties of a novel 14-mer antiangiogenic peptide (14-MAP) derived from N-terminal 14kDa buffalo prolactin, followed by an exploration of its mode of action. 14-MAP at the picomolar concentration inhibited VEGF- and bradykinin (an autacoid peptide expressed in vascular tissues in pathophysiology)-stimulated endothelial nitric oxide (eNO) production, cell migration and proliferation in endothelial cells and vessel development in chick embryo. The crucial inhibitory effects of the peptide, however, were presented on the bradykinin-dependent angiogenic properties. Moreover, the interference of 14-MAP with the eNO synthase (eNOS)-cyclic GMP pathway was identified. A combination of low dose of Avastin, a widely used drug targeting VEGF-dependent angiogenesis, and 14-MAP significantly reduced tumor size in a mouse model of human colon cancer. These results suggest that 14-MAP, a bradykinin- and eNOS-dependent antiangiogenic peptide, can be useful for overcoming the limitation of VEGF-targeted antiangiogenic therapy in cancer patients.