Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner

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• 作者：Saghir Akhtar ; Ahmed Z El-Hashim ; Bindu Chandrasekhar ; Sreeja Attur ; Ibrahim F. Benter
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：May 2, 2016
• 年：2016
• 卷：13
• 期：5
• 页码：1575-1586
• 全文大小：628K
• 年卷期：0
• ISSN：1543-8392

文摘

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.