DISSOCIATION BETWEEN PHOSPHODIESTERASE INHIBITION AND ANTIPROLIFERATIVE EFFECTS OF PHOSPHODIESTERASE INHIBITORS ON THE DAMI CELL-LINE

Phosphodiesterase (PDE) inhibitors were shown to inhibit proliferation of various cell types. The present investigation was designed to stud y the activity of selective PDE inhibitors (8-MeoMIX, milrinone, trequ insin, rolipram, RO-201724, zaprinast, and MY-5445) on the proliferati on of the Dami cell line in relation to their effects on cAMP levels a nd PDE isoenzymes isolated from Dami cells. All compounds, except 8-Me oMIX, elicited antiproliferative effects. Trequinsin, RO-201724, and M Y-5445 (100 mu M) were found to inhibit cell growth up to 60%, 83%, an d 85%, respectively; milrinone, rolipram and zaprinast elicited only w eak effects (19-21% at 100 mu M). Their growth-inhibitory effects coul d not be related to their effects on cAMP levels. In addition, althoug h PDE type III and IV inhibitors potentiated cAMP formation due to ade nylycyclase activation, no potentiation could be observed when conside ring their antiproliferative effect. Separation and characterization o f PDE of Dami cells revealed the existence of types III, IV, and V iso enzymes. The PDE inhibition found for the PDE inhibitors could not exp lain their antiproliferative effects. The lack of correlation with cAM P concentrations or PDE inhibition and the high concentrations needed to elicit antiproliferative effects suggest the implication of other p arameters, such as cytotoxicity or lipophilicity, or other targets in addition to PDE for the PDE inhibitors tested. Lipophilicity did not s eem to be of importance in antiproliferative effects. In contrast, cyt otoxic effects, in particular those of trequinsin and MY-5445, could p artially explain their negative action on cell growth. (C) 1997 Elsevi er Science Inc.