3',5'-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition.
Isoenzymes of 3',5'-cyclic nucleotide phosphodiesterase (PDE) have been characterized in B16 murine melanoma cells and MCF-7 human mammary carcinoma cells. Separation of soluble phosphodiesterase activity by fast protein liquid chromatography on a Mono-Q column resolved three isoenzymes, MCF-7 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a cyclic GMP-activable isoenzyme (PDE-II), and a cyclic AMP-specific isoenzyme (PDE-IV). B16 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a Ca2+/calmodulin-activated isoenzyme (PDE-I), and a cyclic AMP-specific isoenzyme (PDE-IV). A series of PDE inhibitors was tested for their activity spectrum on PDE isoenzymes. Inhibition of PDE activity in B16 cells by the new compound DC-TA-46, was found to result specifically from PDE-IV inhibition [50% inhibition (IC50) = 0.03 microM]. Much lower inhibitory activity was observed for DC-TA-46 toward PDE-I (IC50 = 5 microM) and PDE-V (IC50 = 14 microM). DC-TA-46 was found to inhibit growth of B16 melanoma and MCF-7 mammary carcinoma cells dose dependently (B16: IC50 = 1.7 microM, MCF-7: IC50 = 2 microM). At 2 microM concentration, growth inhibition of B16 melanoma cells was 60%, concomitant with a decrease in PDE activity of 63% and an increase in cAMP level of 59%. In contrast, incubation with inhibitors specific for PDE-I and PDE-V resulted only in marginal or undetectable growth inhibition. The results suggest a correlation between PDE-IV inhibition and growth inhibition. PDE-IV thus appears to be a potential new target for antiproliferative treatment.
Department of Internal Medicine I, University of Freiburg, Germany.
M
M
Drees
R
R
Zimmermann
G
G
Eisenbrand
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000837:Anion Exchange Resins; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002458:Cell Fractionation; D002852:Chromatography, Ion Exchange / Q000379:methods; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011621:Pteridines / Q000494:pharmacology*; D012117:Resins, Synthetic; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000837:Anion Exchange Resins; D000970:Antineoplastic Agents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011621:Pteridines; D012117:Resins, Synthetic; C081896:7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine; C042855:Mono Q; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases