title: Development of new inhibitors for N-acylethanolamine-hydrolyzing acid amidase as promising tool against bladder cancer.
abstract: The endocannabinoid system is a signaling system involved in a wide range of biological effects. Literature strongly suggests the endocannabinoid system role in the pathogenesis of cancer and that its pharmacological activation produces therapeutic benefits. Last research promotes the endocannabinoid system modulation by inhibition of endocannabinoids hydrolytic enzymes instead of direct activation of endocannabinoid receptors to avoid detrimental effects on cognition and motor control. Here we report the identification of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors able to reduce cell proliferation and migration and cause cell death on different bladder cancer cell lines. These molecules were designed, synthesized and characterized and active compounds were selected by a fluorescence high-throughput screening method set-up on human recombinant NAAA that also allows to characterize the mechanism of inhibition. Together our results suggest an important role for NAAA in cell migration and in inducing tumor cell death promoting this enzyme as pharmacological target against bladder cancer.
authors.affiliation: Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan, Italy; Università Vita-Salute San Raffaele, Via Olgettina 60, Milano, Italy. Electronic address: vago.riccardo@hsr.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vago
authors.affiliation: Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan, Italy. Electronic address: bettiga.arianna@hsr.it.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bettiga
authors.affiliation: Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan, Italy; Università Vita-Salute San Raffaele, Via Olgettina 60, Milano, Italy. Electronic address: andrea.salonia@hsr.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Salonia
authors.affiliation: Dipartimento di Scienze Biomediche e Cliniche "Luigi Sacco", Via G.B. Grassi 74, Università degli Studi di Milano, Italy. Electronic address: pierangela.ciuffreda@unimi.it.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Ciuffreda
authors.affiliation: Dipartimento di Scienze Biomediche e Cliniche "Luigi Sacco", Via G.B. Grassi 74, Università degli Studi di Milano, Italy. Electronic address: roberta.ottria@guest.unimi.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ottria
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004983:Ethanolamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004983:Ethanolamines; C022203:N-acylethanolamines; D011994:Recombinant Proteins; D000581:Amidohydrolases; C523108:NAAA protein, human
keywords: Bladder cancer; Endocannabinoid; Enzyme inhibition; N-acylethanolamine-hydrolyzing acid amidase