Antiproliferative action of dopamine and norepinephrine in neuroblastoma cells expressing the human dopamine transporter.

The classical catecholamine transmitters dopamine and norepinephrine are also involved in neurodevelopment and neuron cell death. These effects are thought to be mediated by receptors coupled to intracellular second messengers and by oxidative stress, respectively. Using human SK-N-MC neuroblastoma cells stably transfected with the dopamine or norepinephrine transporter, we show that catecholamines have profound effects on cell viability not mediated by any of the above mechanisms. Low micromolar concentrations of dopamine or norepinephrine (1-10 muM) affected cell growth depending on the expression level of plasmalemmal transport. The growth inhibition was accompanied by a profound effect on the cell cycle profile with an arrest in G, as determined by flow cytometry measuring DNA content. In a proportion of cells, apoptosis was present. Various antioxidants did not prevent the catecholamine effect, and there was no indication of accumulation of reactive oxygen species (as determined by hydroethidine, dichlorofluorescein, and the inactivation-reactivation pattern of aconitase), ruling out involvement of oxidative stress. Reversal by FeCl3 and parallel effects of the iron-chelator deferoxamine suggest that the catecholamine action was related to intracellular iron chelation. This novel biological action of dopamine and norepinephrine unrelated to neurotransmitter receptors, second messengers, or oxidative stress may be important for cell differentiation during neurodevelopment and survival of differentiated neurons.