ADENOSINE AND ADENINE-NUCLEOTIDES INHIBIT THE AUTONOMOUS AND EPIDERMAL GROWTH FACTOR-MEDIATED PROLIFERATION OF CULTURED HUMAN KERATINOCYTES

Previous investigations have shown disparate effects of adenine nucleo tides on epidermal cell proliferation. Our present study demonstrates that adenosine and its related nucleotides (ATP, ADP, AMP) are antipro liferative for normal human epidermal keratinocytes cultured in the ab sence or presence of exogenous epidermal growth factor. Furthermore, t he inhibitory effects of these compounds occur at concentrations less than 100 mu M, are reversible, and do nor affect the viability of the keratinocyte cultures. Our current investigation also demonstrates tha t both selective and nonselective adenosine receptor agonists are them selves approximately as potent as keratinocyte proliferation inhibitor s, but are all less potent inhibitors than adenosine. These observatio ns are consistent with the theory that adenosine mediates its antiprol iferative response via a novel or more poorly characterized adenosine purinoreceptor subclass. Moreover, our present study demonstrates that ATP and ATP-gamma-S are significantly more potent antiproliferative a gents than either alpha,beta-methylene ATP or beta,gamma-methylene ATP . Based on previous studies that have demonstrated that P-2Y purinorec eptors possess this type of ligand specificity and that the P-2Y purin oreceptor may be expressed by keratinocyte cultures, we propose that A TP may mediate its antiproliferative effects via this purinoreceptor. Collectively, our results indicate that adenosine and adenine nucleoti des abrogate exogenous epidermal growth factor-dependent and -independ ent keratinocyte proliferation at submillimolar concentrations and may be important physiologic regulators of keratinocyte growth in vivo. F urther, these results suggest that these or related compounds may have application as treatments for epidermal proliferative pathologies in which the epidermal growth factor receptor-signaling pathway has been activated.