Inhibition of stimulated Jurkat cell adenosine 3′,5′-cyclic monophosphate synthesis by the immunomodulatory compound HR32577Abbreviations: PGE2, prostaglandin E2; FKN, forskolin; CTX, cholera toxin; cAMP, adenosine 3′,5′-cyclic monophosphate; IBMX, 3-isobutyl-1-methylxanthine; NCA, niclosamide; FCCP, carbonyl cyanide p-trifluoromethoxyphenyl hydrazone; DHO-DH, dihydroorotate dehydrogenase; IL-2, interleukin-2; and HBSS, Hanks’ balanced salt solution

Autor: Erik Ruuthb, Richard A. Williamson, Yea Christopher Martyn, T. Andrew Thomson, Elizabeth Anne Kuo, Robert Westwood, Adam P. Curnock
Rok vydání: 2001
Předmět:
Zdroj: Biochemical Pharmacology. 61:227-235
ISSN: 0006-2952
DOI: 10.1016/s0006-2952(00)00552-9
Popis: HR325 (2-cyano-3-cyclopropyl-3-hydroxy- N -[3′-methyl-4′(trifluoromethyl)-phenyl]-propenamide) is an immunomodulatory compound through pyrimidine biosynthesis inhibition with antiproliferative properties which was derived from the isoxazol compound A77 1726 [2-cyano-3-cyclopropyl-3-hydroxy-enoic acid (4-trifluoromethylphenyl)-amide]. During studies of the effects on early signal transduction events of this type of compound, it was found that HR325 dose-dependently inhibited adenosine 3′,5′-cyclic monophosphate (cAMP) synthesis by Jurkat cells stimulated with prostaglandin E 2 , (PGE 2 ), cholera toxin (CTX), or forskolin (FKN). The potency of inhibition by HR325 of FKN-stimulated cells ( ic 50 30.4 μM) was approximately 3-fold higher than that of the other agonists (11.6 and 11.7 μM) and was independent of time of preincubation for both PGE 2 and FKN. Interestingly, A77 1726, an analogue of HR325, displayed a markedly different profile of stimulus-dependent potencies. The inhibition of cAMP synthesis by HR325 when stimulated by both PGE 2 and FKN was unaffected by glucose supplementation, in contrast to HR325-inhibited ATP levels, which were restored under such conditions. Further studies revealed that HR325 reduced intracellular ATP levels by uncoupling oxidative phosphorylation, albeit with a 1000-fold lower potency than the antihelmintic drug niclosamide. In addition, glucose supplementation experiments showed that, in contrast to HR325, the niclosamide-mediated reduction of ATP levels was wholly responsible for its inhibition of PGE 2 - and FKN-stimulated cAMP synthesis.
Databáze: OpenAIRE
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