Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner.
Mol Pharm
; 13(5): 1575-86, 2016 05 02.
Article
em En
| MEDLINE
| ID: mdl-26985693
ABSTRACT
The effects of naked polyamidoamine (PAMAM) dendrimers on renin-angiotensin system (RAS) signaling via Angiotensin (Ang) II-mediated transactivation of the epidermal growth factor receptor (EGFR) and the closely related family member ErbB2 (HER2) were investigated. In primary aortic vascular smooth muscle cells, a cationic fifth-generation (G5) PAMAM dendrimer dose- and time-dependently inhibited Ang II/AT1 receptor-mediated transactivation of EGFR and ErbB2 as well as their downstream signaling via extracellular-regulated kinase 1/2 (ERK1/2). Inhibition even occurred at noncytotoxic concentrations at short (1 h) exposure times and was dependent on dendrimer generation (G7 > G6 > G5 > G4) and surface group chemistry (amino > carboxyl > hydroxyl). Mechanistically, the cationic G5 PAMAM dendrimer inhibited Ang II-mediated transactivation of EGFR and ErbB2 via inhibition of the nonreceptor tyrosine kinase Src. This novel, early onset, intrinsic biological action of PAMAM dendrimers as inhibitors of the Ang II/AT1/Src/EGFR-ErbB2/ERK1/2 signaling pathway could have important toxicological and pharmacological implications.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Poliaminas
/
Polímeros
/
Angiotensina II
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Ativação Transcricional
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Receptor ErbB-2
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Dendrímeros
/
Receptores ErbB
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article