title: Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner.
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.
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
authors.forename: Ahmed Z
authors.initials: AZ
authors.lastname: El-Hashim
authors.forename: Bindu
authors.initials: B
authors.lastname: Chandrasekhar
authors.forename: Sreeja
authors.initials: S
authors.lastname: Attur
authors.affiliation: Faculty of Medicine, Eastern Mediterranean University , Famagusta, North Cyprus.
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D050091:Dendrimers / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000804:Angiotensin II; D050091:Dendrimers; D066246:ErbB Receptors; D011073:Polyamines; D011108:Polymers; D044140:Receptor, Angiotensin, Type 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C531249:Poly(amidoamine); C483803:Egfr protein, rat; C483804:Erbb2 protein, rat
keywords: Angiotensin II; EGFR; ErbB2; PAMAM; Src; biological activity; toxicity