title: Activation of the A3 adenosine receptor affects cell cycle progression and cell growth.
abstract: The A3 adenosine receptor has been implicated in modulation of cell growth. As a first step to the characterization of the underlying mechanisms, we exposed Chinese hamster ovary (CHO) cells transfected with the human A3 receptor (A3R-CHO) to selective A3 receptor ligands. At micromolar concentrations, the A3 agonists N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and its 2-chloro derivative Cl-IB-MECA reduced cell number, with no effects on either parental CHO cells (not expressing any adenosine receptor), or CHO cells transfected with the human A1 receptor. Cl-IB-MECA also reduced cell number in the human HEK293 cell line transfected with the human A3 receptor cDNA as opposed to the respective untransfected wild-type cells. In A3R-CHO, agonist-induced effects were antagonized by nanomolar concentrations of A3 antagonists, including the triazoloquinazoline derivative MRS 1220, the dihydropyridine derivative MRS 1191, and the triazolonaphthyridine derivative L-249,313. A3 agonist-induced effects were not due to modulation of cell adhesion, nor to necrosis or apoptosis. Growth curves revealed highly impeded growth, and flow-cytometric analysis showed markedly reduced bromodeoxyuridine incorporation into nuclei. The effect on cell cycle was completely antagonized by MRS1191. Hence, activation of the human A3 receptor in A3R-CHO results in markedly impaired cell cycle progression, suggesting an important role for this adenosine receptor subtype in cell cycle regulation and cell growth.
authors.affiliation: Institute of Pharmacological Sciences, School of Pharmacy, University of Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Brambilla
authors.forename: F
authors.initials: F
authors.lastname: Cattabeni
authors.forename: S
authors.initials: S
authors.lastname: Ceruti
authors.forename: D
authors.initials: D
authors.lastname: Barbieri
authors.forename: C
authors.initials: C
authors.lastname: Franceschi
authors.forename: Y C
authors.initials: YC
authors.lastname: Kim
authors.forename: K A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: K N
authors.initials: KN
authors.lastname: Klotz
authors.forename: M J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: M P
authors.initials: MP
authors.lastname: Abbracchio
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects* / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004095:Dihydropyridines / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology
chemical_list: C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D000970:Antineoplastic Agents; D004095:Dihydropyridines; C107728:MRS 1191; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D014230:Triazoles; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D000262:Adenylyl Cyclases; D000241:Adenosine