Recent clinical evidence revealed that the use of beta-blockers such as
propranolol, prior to diagnosis or concurrently with
chemotherapy, could increase relapse-free and overall survival in
breast cancer patients. We therefore hypothesized that
propranolol may be able to increase the efficacy of
chemotherapy either through direct effects on
cancer cells or via anti-angiogenic mechanisms. In vitro proliferation assay showed that
propranolol (from 50-100 μM) induces dose-dependent anti-proliferative effects in a panel of 9 human
cancer and "normal" cell lines.
Matrigel assays revealed that
propranolol displays potent anti-angiogenic properties at non-toxic concentrations (less than 50 μM) but exert no vascular-disrupting activity. Combining chemotherapeutic drugs, such as
5-fluorouracil (5-FU) or
paclitaxel, with
propranolol at the lowest effective concentration resulted in synergistic, additive or antagonistic effects on cell proliferation in vitro depending on the cell type and the dose of
chemotherapy used. Interestingly,
breast cancer and vascular endothelial cells were among the most responsive to these combinations. Furthermore,
Matrigel assays indicated that low concentrations of
propranolol (10 - 50 μM) potentiated the anti-angiogenic effects of
5-FU and
paclitaxel. Using an orthotopic xenograft model of
triple-negative breast cancer, based on s.c injection of
luciferase-expressing MDA-MB-231 cells in the mammary fat pad of nude mice, we showed that
propranolol, when used alone, induced only transient anti-
tumor effects, if at all, and did not increase median survival. However, the combination of
propranolol with
chemotherapy resulted in more profound and sustained anti-
tumor effects and significantly increased the survival benefits induced by
chemotherapy alone (+19% and +79% in median survival for the combination as compared with 5-FU alone and
paclitaxel alone, respectively; p less than 0.05). Collectively our results show that
propranolol can potentiate the anti-angiogenic effects and anti-
tumor efficacy of
chemotherapy. The current study, together with retrospective clinical data, strongly suggests that the use of
propranolol concurrently with
chemotherapy may improve the outcome of
breast cancer patients, thus providing a strong rationale for the evaluation of this
drug combination in prospective clinical studies.