β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma

Background: The use of beta-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether beta-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. Methods: Seven beta-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma. Results: Three beta-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. beta-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, beta-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, beta-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01). Conclusion: beta-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.