Chemopreventative properties of β‐blockers

Abstract

Recently carvedilol, a β‐AR GRK/β‐arrestin biased agonist, was shown to have cancer preventative effects; yet, atenolol, a β2‐AR inverse agonist, was less potent and efficacious. These disparate results lead to the hypothesis that the GRK/β‐arrestin biased agonist β‐blockers act as chemopreventive agents. JB6 P+ cells are an established chemoprevention model that is transformable by epidermal growth factor (EGF). Thus, JB6 P+ cells treated with 10 ng/mL EGF were utilized to screen partial agonist, inverse agonist, neutral antagonist, and biased agonist β‐blockers for inhibition of growth in soft agar. Additionally, parallel cytotoxicity assays were conducted for each β‐blocker to ensure that any observable inhibition is not due to cell death. EGF‐mediated colony formation is fully inhibited by carvedilol with a LogIC50 of ‐6.365 ± 0.158 and partially (47.9% ± 7.6%) inhibited by atenolol with a LogIC50 of ‐5.037 ± 0.266 at non‐toxic concentrations. Preliminary studies indicate that: 1) nebivolol acts similarly to carvedilol;2) acebutolol, ICI 118,551, metoprolol, and bucindolol have little to no effect; and 3) labetalol, carazolol, and propranolol have effects similar to atenolol. Expression of only β2‐ARs can explain the changes in potency, but the differences in efficacy suggest a unique biological effect. Thus, categorization of the β‐blockers by type paradoxically indicates that β‐blockers that can activate the EGF receptor are the most potent inhibitors of EGF‐mediated transformation of JB6 P+ cells and thus my serve as chemopreventative agents.