Diazepam Inhibits Forskolin‐Stimulated Adenylyl Cyclase Activity in Human Tumour Cells
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abstract
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=5.7×10−12M), is similar to the receptor mediated phase observed in the rat brain. At micromolar concentrations of diazepam (EC50=1.8×10−4M), 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=5.2×10−4M) 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.
