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 study the activity of selective PDE inhibitors (8-MeoMIX, milrinone, trequinsin, rolipram, RO-201724, zaprinast, and MY-5445) on the proliferation of the Dami cell line in relation to their effects on cAMP levels and PDE isoenzymes isolated from Dami cells. All compounds, except 8-MeoMIX, elicited antiproliferative effects. Trequinsin, RO-201724, and MY-5445 (100 microM) were found to inhibit cell growth up to 60%, 83%, and 85%, respectively; milrinone, rolipram and zaprinast elicited only weak effects (19-21% at 100 microM). Their growth-inhibitory effects could not be related to their effects on cAMP levels. In addition, although PDE type III and IV inhibitors potentiated cAMP formation due to adenylycyclase activation, no potentiation could be observed when considering their antiproliferative effect. Separation and characterization of PDE of Dami cells revealed the existence of types III, IV, and V isoenzymes. The PDE inhibition found for the PDE inhibitors could not explain their antiproliferative effects. The lack of correlation with cAMP concentrations or PDE inhibition and the high concentrations needed to elicit antiproliferative effects suggest the implication of other parameters, such as cytotoxicity or lipophilicity, or other targets in addition to PDE for the PDE inhibitors tested. Lipophilicity did not seem to be of importance in antiproliferative effects. In contrast, cytotoxic effects, in particular those of trequinsin and MY-5445, could partially explain their negative action on cell growth.
Zurbonsen
K
K
INSERM U.300, Montpellier, France.
Michel
A
A
Vittet
D
D
Bonnet
P A
PA
Chevillard
C
C
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000527:Alprostadil; D002455:Cell Division / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D007546:Isoquinolines / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007947:Leukemia, Megakaryoblastic, Acute; D020105:Milrinone; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010793:Phthalazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D007527:Isoenzymes; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D011728:Pyridones; D011760:Pyrrolidinones; D044005:Tetrahydroisoquinolines; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C035964:trequinsin; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D000527:Alprostadil; C052490:MY 5445; D020105:Milrinone; D020889:Rolipram