Abstract 2555: Drug repositioning: Propanolol potentiates the anticancer efficacy of chemotherapeutic agents through modulation of angiogenesis
Authors: Ciccolini Joseph , Pasquier Eddy , Fanciullino Raphaelle , Serdjebi Cindy , Mas Cecilia , Giacometti Sarah , Kavallaris Maria , André Nicolas 
Published: June 2012

Abstract
Background: Recently, the beta-blocker propranolol was found to be of clinical benefit in the treatment of severe hemangioma of infancy. Although its precise mechanisms of action have not been fully elucidated, it could involve vasoconstriction, inhibition of angiogenic signalling and direct induction of apoptosis in endothelial cells. Here, we evaluate whether propranolol could improve the antitumor efficacy of standard chemotherapeutic agents. Methods: The impact of adding concomitantly propranolol to 5-FU was first investigated on a representative panel of human colorectal, breast and medulloblastoma cell lines (SW620, HT29, BT474, MDA231, HTB186). Their effects on angiogenesis were further investigated in 2 different endothelial cell lines (HMEC-1 and BMH29L), by Matrigel assay using time-lapse videomicroscopy. The combination treatment was then evaluated in 2 different xenograft mouse models of human breast cancer. Results: Propranolol showed little cytotoxic activity at clinically relevant concentrations in vitro. Results from combination studies of 5-FU and propranolol were cell line-dependent and ranged from no significant effect (HTB186, SW620), to additivity (HT29, BT474), and synergism (MDA-231). Increase in early and late apoptosis, with accumulation in the sub-G0/G1 phase, was observed in the most sensitive models exposed to the combination of 5-FU and propranolol. In endothelial cells, combination index calculations revealed a synergistic effect on angiogenesis (CI = 0.54 ± 0.09). For instance, 5-FU and propranolol alone (50 µM) inhibited the differentiation of HMEC-1 cells into vascular structures by 10 and 27%, respectively while the equimolar combination of drugs resulted in a 52% inhibition (p&lt;0.001). In vivo, all treatments were well tolerated. In the MDA-231 orthotopic model, 5-FU (30 mg/kg 3QW × 5wks) alone achieved only mild reduction in tumor size (−38% at Day-30; n.s.) as compared with control animals. Combining 5-FU with low (0.15 mg/kg) and high (7 mg/kg) doses of propranolol led to a further 49 and 70% reduction in tumor growth, respectively (Day-30; p&lt;0.05). Accordingly, the combination led to a marked increase in animal survival. Mean survival at Day-50 increased from 0% (control) and 44% (5-FU) to 77% (combination). Finally, additional in vitro angiogenesis experiments revealed a powerful synergism between propranolol and paclitaxel. Further investigations are currently underway to validate the potential efficacy of the propranolol/paclitaxel combination in vitro and in vivo. Conclusions & perspectives: This study provides strong evidence that propranolol can improve the antitumor efficacy of major cytotoxic drugs in vitro and in vivo. Propranolol mediates these effects, at least in part, through anti-angiogenic mechanisms. Additional studies are currently ongoing to refine the mechanisms of action of propranolol.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2555. doi:10.1158/1538-7445.AM2011-2555