Background: In recent years, a large number of clinical and epidemiological studies have revealed the anticancer activity of propranolol in solid tumors, though the underline mechanism is yet to be clarified.
Methods:The proliferation of bladder cancer cells treated with propranolol was detected by MTS assays.In vivo tumor xenograft experiments were used to observe the effect of propranolol on bladder cancer growth in mice. The expression levels of Na + /H + exchanger (NHE1) was measured by western blot. The frequency of CD8 + T cells and CD4 + T cells were detected via flow cytometry.Results: In this study, propranolol inhibited the expression of NHE1 and sequentially led to a decrease of intracellular pH to 5.88 in MB49 cells and 6.85 in 5637 cells, thereafter, inhibited cell viability and induced apoptosis. Furthermore, propranolol inhibited the growth of bladder cancer in mice xenograft model. Flow cytometry found that the frequency of CD8 + T cells (34.58±2.11 vs. 32.34±0.6, P=0.35) and CD4 + T cells (57.80±2.45 vs. 51.44±0.79, P=0.06) in the spleen did not change compared with the control group, while the expression of IFN-γ, GZMB and T-bet secreted by CD8 + T cells increased respectively (IFN-γ 7.3±0.17 vs.
Preclinical and early clinical mechanistic studies of antitumor activity from the beta-adrenergic receptor (β-AR) blocker propranolol have revealed both cell signaling and immune function pathway effects.Intertumoral studies were performed using propranolol, a β 1 -AR selective agent (atenolol) and a β 2 -AR selective agent (ICI 118,551) in a preclinical in vivo model, as a step to dissect the contribution of cell signaling and CD8 + immunological effects on anticancer activity. We found that repression of β 2 -AR but not β 1 -AR signaling selectively suppressed cell viability and inhibited xenograft growth in vivo. Moreover, Western blot analysis indicated that the phosphorylation levels of AKT/MEK/ERK were signi cantly decreased following the inhibition of β 2 -AR. Furthermore, propranolol was found to activate tumor microenvironment with increased intratumoral frequency of CD8 + T cells, whereas neither selective β 1 nor β 2 -AR blockers had a signi cant effect on the tumor immune microenvironment. Thus, the results of this mechanistic dissection support a predominant role of cell signaling, rather than the activation of CD8 + T cells, as the basis for propranolol antitumor activity.
Key MessageMolecular signaling of AKT/MAPK pathway contributes to propranolol caused cancer control. CD8+ T cells in tumor microenvironment were activated upon propranolol exposure.The basis for propranolol antitumor activity was predominantly dependent on cell signaling, rather than the activation of CD8 + T cells
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