Journal
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Volume 361, Issue 3, Pages 225-234Publisher
SPRINGER VERLAG
DOI: 10.1007/s002109900186
Keywords
adenosine; adenosine receptor; human A(3); CHO transfected cells; HEK293 transfected cells; cell growth modulation; cell cycle
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Funding
- Intramural NIH HHS [ZIA DK031117] Funding Source: Medline
- NIMH NIH HHS [01MH30003] Funding Source: Medline
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The A(3) 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 A(3) receptor (A(3)R-CHO) to selective A(3) receptor ligands. At micromolar concentrations, the A(3) agonists N-6-(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 A(1) receptor. Cl-IB-MECA also reduced cell number in the human HEK293 cell line transfected with the human A(3) receptor cDNA as opposed to the respective untransfected wild-type cells. In A(3)R-CHO, agonist-induced effects were antagonized by nanomolar concentrations of A(3) antagonists, including the triazoloquinazoline derivative MRS1220, the dihydropyridine derivative MRS 1191, and the triazolonaphthyridine derivative L-249,313, A(3) 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 A(3) receptor in A(3)R-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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