3',5'-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition.

Abstract

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.

• Authors: M Drees, R Zimmermann, G Eisenbrand
• Journal: Cancer research (Cancer Res) Vol. 53 Issue 13 Pg. 3058-61 (Jul 01 1993) ISSN: 0008-5472 [Print] United States
• PMID: 8391385 (Publication Type: Journal Article)

Chemical References

• Anion Exchange Resins
• Antineoplastic Agents
• Isoenzymes
• Phosphodiesterase Inhibitors
• Piperazines
• Pteridines
• Resins, Synthetic
• 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine
• Mono Q
• 2',3'-Cyclic-Nucleotide Phosphodiesterases

Topics

• 2',3'-Cyclic-Nucleotide Phosphodiesterases (antagonists & inhibitors, metabolism)
• Animals
• Anion Exchange Resins
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Division (drug effects)
• Cell Fractionation
• Chromatography, Ion Exchange (methods)
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism)
• Melanoma, Experimental (drug therapy, enzymology, pathology)
• Mice
• Phosphodiesterase Inhibitors (pharmacology)
• Piperazines (pharmacology)
• Pteridines (pharmacology)
• Resins, Synthetic
• Tissue Distribution
• Tumor Cells, Cultured