(R,R')-4-methoxy-1-naphthylfenoterol (MNF) inhibits
cancer cell proliferation in vitro through cell-type specific modulation of β2-adrenergic receptor and/or
cannabinoid receptor function. Here, we report an investigation into antitumor activity of MNF in rat C6
glioma cells. The potent antiproliferative action of MNF in these cells (IC50 of ∼1 nmol/L) was refractory to pharmacological inhibition of β2-adrenergic receptor while a synthetic inverse agonist of
cannabinoid receptor 1 significantly blocked MNF activity. The antitumor activity of MNF was then assessed in a C6
glioblastoma xenograft model in mice. Three days after subcutaneous implantation of C6 cells into the lower flank of nude mice, these animals were subjected to i.p.
injections of saline or MNF (2 mg/kg) for 19 days and
tumor volumes were measured over the course of the experiment. Gene expression analysis, quantitative RT-PCR and immunoblot assays were performed on the
tumors after treatment. Significant reduction in mean
tumor volumes was observed in mice receiving MNF when compared with the saline-treated group. We identified clusters in expression of genes involved in cellular proliferation, as well as molecular markers for
glioblastoma that were significantly downregulated in
tumors of MNF-treated mice as compared to saline-injected controls. The efficacy of MNF against C6
glioma cell proliferation in vivo and in vitro was accompanied by marked reduction in the expression of cell cycle regulator
proteins. This study is the first demonstration of MNF-dependent
chemoprevention of a
glioblastoma xenograft model and may offer a potential mechanism for its anticancer action in vivo.