Polydeoxyribonucleotides enhance the proliferation of human skin fibroblasts: Involvement of A(2) 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 c ompounds are reported both to synergize with growth factor, and to act dire ctly on purinergic receptor inducing per se a proliferative response. It wa s suggested that cell growth enhancement could be mediated by the A(2) puri nergic receptor activation. Here we report that a polydeoxyribonucleotide ( PDRN) and adenosine are able to increase, the growth rate of human skin fib roblasts in primary cultures. The proliferative activity exerted by PDRN wa s significantly counteracted by the A(2) antagonist 3, 7-Dimethyl-1-proparg ylxanthine (DMPX), but not by the A(1) antagonist 8-cyclopentyl-1, 3-diprop ylxanthine (PD 1 16,948, DPCPX). Accordingly, the trophic action of PDRN wa s 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 t hat PDRN and adenosine increased the concentration of cytosolic calcium ion s. The PDRN-evoked calcium rise was dose- dependent and DMPX sensitive. Tak en together, our results suggest that PDRN may operate as a pro-drug provid ing the cultured cells with an effective amount of mitogenic deoxyribonucle otides, deoxyribonucleosides and bases; moreover, cell proliferation enhanc ement that has been induced by PDRN seems to be mediated, at least in part, by the activation of purinergic receptors of the Az subtype.