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.
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