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

Background: The use of β -blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether β -blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. Methods: Seven β -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 β -blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. β -blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo , β -blockers alone transiently slowed tumour growth as compared with vehicle only ( P