α‐Adrenoceptor stimulation attenuates melanoma growth in mice

Recently, β-adrenoceptor blockade has emerged as a potential strategy to inhibit melanoma growth. It remains to be ascertained whether β-adrenoceptor stimulation by circulating catecholamines increases melanoma growth in mice.B16F10 melanoma-bearing mice were used to evaluate effects of adrenaline and specific adrenoceptor (AR) ligands on tumour volume. AR expression and effects of AR ligands on cell viability, production of mitochondrial reactive oxygen species (mROS), and proliferation activity in B16F10 cells, were determined by biochemical analyses.Real-time polymerase chain reaction (qPCR) analyses revealed that B16F10 cells express α1B-, α2A-, α2B- and β2-ARs. We found that treatment with the α- and β-AR agonist adrenaline or with the synthetic catecholamine isoprenaline, which selectively stimulates β-ARs, did not affect melanoma growth. Conversely, adrenaline reduced tumour growth in mice cotreated with propranolol, a β1β2-AR antagonist. Adrenaline had no effect in tumour-bearing β1β2-AR knockout mice, in which β1- and β2-ARs are lacking, but it reduced tumour growth when co-administered with propranolol suggesting that tumour β2-ARs negatively regulate adrenaline antitumour activity. Additionally, we found that α1-AR stimulation with cirazoline yielded a decrease in B16F10 melanoma size. These effects on melanoma growth were paralleled by reduced cell viability and proliferation activity as well as increased mROS production in α1-AR-stimulated B16F10 cells. Decreased viability, proliferation and mitochondrial function in B16F10 cells also occurred after α2-AR stimulation by α2-AR agonist ST91.In the B16F10 melanoma model, stimulation of α-AR subtypes yields in vivo and in vitro anticancer activity.