β2 Adrenergic Receptor Agonists Inhibit the Proliferation of 1321N1 Astrocytoma Cells

Abstract

Astrocytomas and glioblastomas have been particularly difficult to treat and refractory to chemotherapy. However, significant evidence has been presented that demonstrates a decrease in astrocytoma cell proliferation subsequent to an increase in cAMP levels. The 1321N1 astrocytoma cell line, as well as other astrocytomas and glioblastomas, expresses β₂-adrenergic receptors (β₂-ARs) that are coupled to G_s activation and consequent cAMP production. Experiments were conducted to determine whether the β₂-AR agonist (R,R′)-fenoterol and other β₂-AR agonists could attenuate mitogenesis and, if so, by what mechanism. Receptor binding studies were conducted to characterize β₂-AR found in 1321N1 and U118 cell membranes. In addition, cells were incubated with (R,R′)-fenoterol and analogs to determine their ability to stimulate intracellular cAMP accumulation and inhibit [³H]thymidine incorporation into the cells. 1321N1 cells contain significant levels of β₂-AR as determined by receptor binding. (R,R′)-fenoterol and other β₂-AR agonists, as well as forskolin, stimulated cAMP accumulation in a dose-dependent manner. Accumulation of cAMP induced a decrease in [³H]thymidine incorporation. There was a correlation between concentration required to stimulate cAMP accumulation and inhibit [³H]thymidine incorporation. U118 cells have a reduced number of β₂-ARs and a concomitant reduction in the ability of β₂-AR agonists to inhibit cell proliferation. These studies demonstrate the efficacy of β₂-AR agonists for inhibition of growth of the astrocytoma cell lines. Because a significant portion of brain tumors contain β₂-ARs to a greater extent than whole brain, (R,R′)-fenoterol, or some analog, may be useful in the treatment of brain tumors after biopsy to determine β₂-AR expression.