title: Diazepam inhibits forskolin-stimulated adenylyl cyclase activity in human tumour cells.
abstract: Previous studies have shown that the benzodiazepine agonist, diazepam, suppresses adenylyl cyclase activity in rat brain, via a G protein-coupled benzodiazepine receptor. Since diazepam binding sites are also present in diverse non-neuronal tissues including tumour cells, its effects on adenylyl cyclase activity were examined in membranes from human MCF-7 (breast cancer) and M-6 (melanoma) cells. Diazepam caused a biphasic and concentration-dependent inhibition of forskolin-stimulated adenylyl cyclase activity in MCF-7 membranes. The first phase of inhibition, at picomolar to nanomolar drug concentrations (EC50=5.7 x 10(-12)M), is similar to the receptor mediated phase observed in the rat brain. At micromolar concentrations of diazepam (EC50= 1.8 x 10(-4)M), the steep decrease in adenylyl cyclase activity may involve a direct action on the enzyme itself, as detected previously in rat brain membranes. Diazepam-induced suppression of adenylyl cyclase activity was also detected in M-6 membranes. However, in contrast to MCF-7 findings, only micromolar concentrations of diazepam (EC50=5.2 x 10(-4)M) inhibited enzyme activity in M-6 membranes. These findings suggest that G protein-coupled benzodiazepine receptors, which mediate inhibition of the adenylyl cyclase-cAMP pathway in the brain, are also expressed in MCF-7 cells.
authors.affiliation: McMaster University, Department of Biomedical Sciences, Hamilton, Ontario, Canada.
authors.forename: L P
authors.initials: LP
authors.lastname: Niles
authors.forename: J
authors.initials: J
authors.lastname: Wang
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology*; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D014151:Anti-Anxiety Agents; D005576:Colforsin; D003975:Diazepam