Polydeoxyribonucleotides enhance the proliferation of human skin fibroblasts:: Involvement of A2 purinergic receptor subtypes

It is well-known that nucleotides, nucleosides and purine/pyrimidine bases enhance cell proliferation in vitro. Nevertheless, the molecular mechanisms involved in this mitogenic activity is still controversial, 'since these compounds are reported both to synergize with growth factor, and to act directly on purinergic receptor inducing per se a proliferative response. It was suggested that cell growth enhancement could be mediated by the A(2) purinergic receptor activation. Here we report that a polydeoxyribonucleotide (PDRN) and adenosine are able to increase, the growth rate of human skin fibroblasts in primary cultures. The proliferative activity exerted by PDRN was significantly counteracted by the A(2) antagonist 3, 7-Dimethyl-1-propargylxanthine (DMPX), but not by the A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine (PD 1 16,948, DPCPX). Accordingly, the trophic action of PDRN was mimicked by the A(2) agonist N-6-[2-(3,5-Dimethoxyphenyl)-2-(methylphenyl)-ethyl] adenosine (DPMA), while the A(1) agonist N-6-Cyclopenthyladenosine (CPA) did not show any effect. In microfluorimetric studies, we observed that PDRN and adenosine increased the concentration of cytosolic calcium ions. The PDRN-evoked calcium rise was dose- dependent and DMPX sensitive. Taken together, our results suggest that PDRN may operate as a pro-drug providing the cultured cells with an effective amount of mitogenic deoxyribonucleotides, deoxyribonucleosides and bases; moreover, cell proliferation enhancement that has been induced by PDRN seems to be mediated, at least in part, by the activation of purinergic receptors of the Az subtype.