Abstract 724: Selective β2-adrenergic receptor agonists inhibit the proliferation of 1321N1 astrocytoma cells

Abstract

Abstract Selective β2-adrenergic receptor agonists inhibit the proliferation of 1321N1 astrocytoma cells Lawrence Toll1, Lucita Jimenez1, Willma Polgar1, Carol Green1, Jason Gow1, Kathleen O'Loughlin1, Michel Bernier2, Irving W. Wainer2 1 SRI International, Menlo Park, CA 2 Intramural Research Program, National Institute of Aging, Baltimore, MD We have reported the synthesis of fenoterol analogs and the characterization of these compounds as selective β2-adrenergic receptor (β2-AR) agonists, which have a broad range of abilities to stimulate cAMP accumulation in β2-AR transfected HEK cells, EC50cAMP. We now report the effect of a series of these compounds on the growth of 1321N1 astrocytoma cells (Table). In the 1321N1 cells, β2-AR stimulation by fenoterol analogs potently inhibited [3H]-thymidine incorporation with IC50 values that correlated with the EC50cAMP values. The effects were blocked by the β2-AR antagonist propranolol and mimicked by the adenylate cyclase activator forskolin. (R,R)-Fenoterol induced G1 arrest with an associated decrease in the proportion of cells in G2 and S phase and modulated the levels of proteins involved in cell division. The results indicate that selective β2-AR agonists may exert unanticipated antitumor effects against neural-derived neoplasms that express the β2-AR.Table.Functional activities of fenoterol analogs. Stimulation of cAMP accumulation was determined in intact HEK cells transfected with the β2-AR. Fenoterol analogs do not inhibit mitogenesis in HEK cells. Inhibition of [3H]-thymidine incorporation was conducted in 1321N1 cells in which the β2-AR is natively expressed. Results expressed as mean ± SD, n = 4.CompoundStimulation of cAMP AccumulationMitogenesis Inhibition EC50 (nM)% StimulationIC50 (nM)Isoproterenol0.20 ± 0.091000.05 ± 0.01(R,R)-fenoterol0.30 ± 0.09123.30 ± 8.790.14 ± 0.07(R,R)-4-methoxyfenoterol0.30 ± 0.23135.70 ± 11.030.17 ± 0.02(R,R)-ethylfenoterol2.80 ± 0.90125.40 ± 5.741.44 ± 0.27(R,R)-1-naphthylfenoterol12.5 ± 3.50129.20± 23.61.57 ± 0.34(R,R)-2-naphthylfenoterol0.40 ± 0.1290.30 ± 9.811.91 ± 0.57(R,R)-4-methoxy-1-naphthyl fenoterol3.90 ± 1.80105.90 ± 11.063.98 ± 0.28 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 724.