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      Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

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          Abstract

          Propranolol (PRO) is a well-known and widely used non-selective beta-adrenergic receptor antagonist (beta-blocker), with a range of actions which are of interest in an oncological context. PRO displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumour cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. In particular there is evidence that PRO is effective at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response. Based on this evidence the case is made for further clinical investigation of the anticancer effects of PRO, particularly in combination with other agents. A number of trials are on-going, in different treatment settings for various cancers.

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          Most cited references178

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          The metastatic niche: adapting the foreign soil.

          The 'seed and soil' hypothesis for metastasis sets forth the concept that a conducive microenvironment, or niche, is required for disseminating tumour cells to engraft distant sites. This Opinion presents emerging data that support this concept and outlines the potential mechanism and temporal sequence by which changes occur in tissues distant from the primary tumour. To enable improvements in the prognosis of advanced malignancy, early interventions that target both the disseminating seed and the metastatic soil are likely to be required.
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            The sympathetic nervous system induces a metastatic switch in primary breast cancer.

            Metastasis to distant tissues is the chief driver of breast cancer-related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the primary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by β-adrenergic signaling, which increased the infiltration of CD11b(+)F4/80(+) macrophages into primary tumor parenchyma and thereby induced a prometastatic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of β-adrenergic signaling induced similar effects, and treatment of stressed animals with the β-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastatic therapies that target the β-adrenergic induction of prometastatic gene expression in primary breast cancers. ©2010 AACR.
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              Derailed endocytosis: an emerging feature of cancer.

              Once engaged by soluble or matrix-anchored ligands, cell surface proteins are commonly sorted to lysosomal degradation through several endocytic pathways. Defective vesicular trafficking of growth factor receptors, as well as unbalanced recycling of integrin- and cadherin-based adhesion complexes, has emerged in the past 5 years as a multifaceted hallmark of malignant cells. In line with the cooperative nature of endocytic machineries, multiple oncogenic alterations underlie defective endocytosis, such as altered ubiquitylation (Cbl and Nedd4 ubiquitin ligases, for example), altered cytoskeletal interactions and alterations to Rab family members. Pharmaceutical interception of the propensity of tumour cells to derail their signalling and their adhesion receptors may constitute a novel target for cancer therapy.
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                Author and article information

                Journal
                Ecancermedicalscience
                Ecancermedicalscience
                ecancermedicalscience
                ecancermedicalscience
                Cancer Intelligence
                1754-6605
                2016
                12 October 2016
                : 10
                : 680
                Affiliations
                [1 ]Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium
                [2 ]The George Pantziarka TP53 Trust, London, UK
                [3 ]GlobalCures, Inc, Newton MA 02459, USA
                [4 ]Oncology Research Centre, Vrije Universiteit Brussel, 1090 Brussels, Belgium
                [5 ]Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
                Author notes
                Correspondence to: Pan Pantziarka. pan.pantziarka@ 123456anticancerfund.org
                Article
                can-10-680
                10.3332/ecancer.2016.680
                5102691
                27899953
                2c889154-1a0f-47ba-be37-fde3a66bcd8b
                © the authors; licensee ecancermedicalscience.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 June 2016
                Categories
                Clinical Study

                Oncology & Radiotherapy
                propranolol,beta-blockers,drug repurposing,redo project
                Oncology & Radiotherapy
                propranolol, beta-blockers, drug repurposing, redo project

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