Carboxyamidotriazole: a novel inhibitor of both cAMP-phosphodiesterases and cGMP-phosphodiesterases.

Abstract

Carboxyamidotriazole (CAI) is a non-cytotoxic anti-tumor drug, which also shows considerable anti-inflammatory effects in a variety of animal models of inflammation. The exact target and mechanism of CAI were not clearly understood yet. In the present study, we demonstrate that CAI is a non-selective phosphodiesterase (PDE) inhibitor, which provides comprehensive inhibitions of both adenosine 3',5'-cyclic monophosphate specific PDE (cAMP-PDE) and guanosine 3',5'-cyclic monophosphate specific PDE (cGMP-PDE) isolated from rat brain, mouse pulmonary tissue, primary mouse peritoneal macrophages, RAW264.7 cells, Lewis lung carcinoma (LLC) cells and lymphocytic leukemia cells (L1210) with moderate potencies (IC50≈0.5-30μM). The comprehensive elimination of PDE activities in living LLC cells by CAI results in accumulation of intracellular cAMP and cGMP, which can be visualized by fluorescence resonance energy transfer (FRET)-based cyclic nucleotide sensors. The stimulation by 30μM CAI yielded ~1.5-fold greater cGMP responses compared with 10μM sildenafil citrate, whereas the influence of 30μM CAI on cAMP levels was similar as that of 100μM 3-isobutyl-1-methylxanthine (IBMX). The non-selective inhibitory effect of CAI on cAMP-PDE and cGMP-PDE increases the likelihood for CAI to affect the balance between the levels of intracellular cyclic nucleotides cAMP and cGMP, then a variety of cellular signaling pathways that regulate cell functions and even related disease processes. When examining the widely proven anti-tumor and anti-inflammatory activities of CAI, it is important to affirm its comprehensive inhibitory effect on PDEs, which makes it superior to some selective PDE inhibitors in a way.

• Authors: Lei Guo, Lifeng Luo, Rui Ju, Chen Chen, Lei Zhu, Juan Li, Xiaoli Yu, Caiying Ye, Dechang Zhang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 746 Pg. 14-21 (Jan 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 25446933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier B.V.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Phosphodiesterase Inhibitors
• Triazoles
• carboxyamido-triazole
• Cyclic AMP
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic GMP

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors, metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cyclic AMP (metabolism)
• Cyclic GMP (metabolism)
• Intracellular Space (drug effects, metabolism)
• Male
• Mice
• Phosphodiesterase Inhibitors (pharmacology)
• Rats
• Signal Transduction (drug effects)
• Triazoles (pharmacology)