Translational Therapeutics

BJC Open article

British Journal of Cancer (2013) 108, 2485–2494. doi:10.1038/bjc.2013.205 www.bjcancer.com
Published online 21 May 2013

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

E Pasquier1,2, J Street1, C Pouchy1,8, M Carre3, A J Gifford1,4, J Murray1, M D Norris1, T Trahair1,5, N Andre2,3,6,9 and M Kavallaris1,7,9

  1. 1Children’s Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, New South Wales 2031, Australia
  2. 2Metronomics Global Health Initiative, Marseille 13005, France
  3. 3Faculty of Pharmacy, INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, 27 Boulevard Jean Moulin, Marseille cedex 05 13385, France
  4. 4Department of Anatomical Pathology (SEALS), Prince of Wales Hospital, Randwick, New South Wales 2031, Australia
  5. 5Sydney Children’s Hospital, Randwick, New South Wales 2031, Australia
  6. 6Department of Hematology and Pediatric Oncology, La Timone University Hospital of Marseille, 264 Rue Saint Pierre, Marseille cedex 05 13385, France
  7. 7Australian Centre for Nanomedicine, School of Chemical Engineering, UNSW, Sydney, New South Wales 2052, Australia

Correspondence: E Pasquier, Dr E Pasquier; E-mail: e.pasquier@ccia.unsw.edu.au

8Current address: Université Pierre et Marie Curie - CNRS UMR 7211 - INSERM U959, Paris, France.

9Both authors contributed equally to this work and should both be considered as senior authors.

Received 13 February 2013; Revised 8 April 2013; Accepted 10 April 2013
Advance online publication 21 May 2013

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Abstract

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<0.01). More importantly, when used in combination, β-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:

  

β-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.

Keywords:

neuroblastoma; β-blockers; chemotherapy; angiogenesis; vincristine; mitochondria