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Aim:To investigate effects of adenosine on cell proliferation and apoptosis in human HepG2 cells.Methods:HepG2 cells were incubated in the presence of adenosine (0.1-5 mmol/L) for 12-48 h,and the effect of adenosine on cell proliferation was evaluated by using 3- (4,5-dimethyl-2-yl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) assay.Hoechst 33342 fluorescent staining.dUTP-fluorescein isothiocyanate (FITC) fluorescence and flow cytometric analysis techniques were used to observe cell apoptosis.The effects of adenosine receptor (A1,A2a,A3 and nonspecific receptor) antagonists (8-cpt,DMPX,MRS1191,and theophylline) and an adenosine transporter protein inhibitor (dipyridamole) on adenosine-induced cell apoptosis were observed.Mitochondrial membrane potential was analyzed using DePsipher fluorescent staining,and caspase activity was detected using a Fluorometric assay kit and a fluorescence microplate reader.Results:Adenosine significantly reduced cell viability in a dose-and time-dependent manner.The cytotoxicity of adenosine was related to the induction of cell apoptosis.Four adenosine receptor antagonists had no eflfect on cell apoptosis.However,dipyridamole significantly reduced the percentage of adenosine-induced apoptotic cells from 27.3% to 7.1% (P＜0.05).At 48 h after treatment,3mmol/L adenosine increased caspase-3 activity 3.5-fold;dipyridamole markedly decreased caspase-3 activity 1.6-fold,and decreased apoptotic cell numbers.When HepG2 cells were treated with 3 mmol/L adenosine.mitochondrial membrane potential and the activity of caspase-8 or-9 remained unchanged.Conclusion:Our results suggest that adenosine.induced apoptosis in HepG2 cells is related to intracellular events rather than cell surface receptors,and that a caspase-3 cascade activation is required,which is not mediated via a mitochondrial pathway.