title: A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro".
abstract: The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Colciago
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milano, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Mornati
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Largo Meneghetti 2, 35131 Padova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milano, Italy.
authors.forename: Luca Franco
authors.initials: LF
authors.lastname: Castelnovo
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti, 9, 20133, Milano, Italy. Electronic address: paola.negricesi@unimi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Negri-Cesi
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D017209:Apoptosis; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms; D012333:RNA, Messenger / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000612079:A175 compound; D058668:Adrenergic alpha-1 Receptor Antagonists; D001572:Benzofurans; D054697:Cytostatic Agents; D004146:Dioxanes; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1
keywords: Adrenergic system; Alpha1D-adrenoreceptor selective antagonist; Anticancer activity; Docetaxel (PubChem CID: 148124); Hormone-resistant human prostate cancer; Phenoxybenzamine hydrochloride (PubChem CID: 5284441); Phenylephrine hydrochloride (PubChem CID: 5284443); “In vitro” cell migration; “In vitro” cell proliferation