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Mol Pharm ; 15(6): 2338-2347, 2018 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-29685037

RESUMEN

The recently reported inhibitory effects of angiotensin 1-7 (Ang-(1-7)) on various cancers indicate its potential use as a therapeutic agent for primary and metastatic cancers. However, its extremely short half-life in the circulation greatly compromises its potential applications. Here, we reported an Ang-(1-7) analogue peptide with the amino and carboxy termini protected by acetylation and amination. The in vitro and in vivo degradation of the resulting analogue, Ang-AA, were determined using high-performance liquid chromatography (HPLC). At the same time, small RNA interference and competition studies were performed to evaluate the specific capacity of Ang-AA to bind to the cell surface Mas receptor. Cell Counting Kit-8 (CCK8), wound-healing, and Boyden chamber assays were performed to investigate the inhibitory effects of Ang-AA on A549 cells. Finally, the synergistic inhibitory effects of Ang-AA and paclitaxel (PTX) on A549 xenografts in mice were observed using animal imaging systems and survival observations. The toxicity of Ang-AA in mice was evaluated. Our results showed that acetylation and amination significantly inhibited the hydrolyzation of Ang-(1-7) in vitro and in vivo. The half-life of Ang-(1-7) in rats was prolonged from 2.4 ± 0.6 min to 238.7 ± 61.3 min ( p < 0.001). The specific binding of Ang-AA to the Mas receptor was well preserved, and Ang-AA exerted significantly greater inhibitory effects on the proliferation, migration, and invasion of A549 cells than Ang-(1-7). The combination of Ang-AA and PTX exhibited a significantly greater synergistic inhibitory effect on A549 xenografts than the combination of Ang-(1-7) and PTX. Ang-AA did not display obvious toxicity in mice. Our findings indicate acetylation and amination is a simple and effective method for producing Ang-(1-7) as a bioactive peptide.


Asunto(s)
Angiotensina I/farmacología , Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Células A549 , Acetilación , Aminación , Angiotensina I/química , Angiotensina I/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Química Farmacéutica , Sinergismo Farmacológico , Semivida , Humanos , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Fragmentos de Péptidos/química , Fragmentos de Péptidos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
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