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Why don't more people engage in green practices in China? A policy-oriented approach to promoting green transformation in five consumption areas
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      Repurposing drugs in oncology (ReDO)—selective PDE5 inhibitors as anti-cancer agents

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of cancers. In particular, evidence is presented that these drugs have potent immunomodulatory activity that warrants clinical study in combination with check-point inhibition.

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          Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells.

          Paolo Serafini, Stephanie Mgebroff, Kimberly Noonan … (2008)
          Tumor-induced T-cell tolerance is a major mechanism that facilitates tumor progression and limits the efficacy of immune therapeutic interventions. Regulatory T cells (Treg) play a central role in the induction of tolerance to tumor antigens, yet the precise mechanisms regulating its induction in vivo remain to be elucidated. Using the A20 B-cell lymphoma model, here we identify myeloid-derived suppressor cells (MDSC) as the tolerogenic antigen presenting cells capable of antigen uptake and presentation to tumor-specific Tregs. MDSC-mediated Treg induction requires arginase but is transforming growth factor-beta independent. In vitro and in vivo inhibition of MDSC function, respectively, with NOHA or sildenafil abrogates Treg proliferation and tumor-induced tolerance in antigen-specific T cells. These findings establish a role for MDSCs in antigen-specific tolerance induction through preferential antigen uptake mediating the recruitment and expansion of Tregs. Furthermore, therapeutic interventions, such as in vivo phosphodiesterase 5-inhibition, which effectively abrogate the immunosuppressive role of MDSCs and reduce Treg numbers, may play a critical role in delaying and/or reversing tolerance induction.
          Article 0 comments Cited 223 times – based on 0 reviews     Review now
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            Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model.

            C. Meyer, A Sevko, M. Ramacher … (2011)
            Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.
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              Myeloid derived suppressor cells – a new therapeutic target in the treatment of cancer

              Robert Wesolowski, Joseph Markowitz, William Carson (2013)
              Myeloid Derived Suppressor Cells (MDSC) are a heterogeneous population of immature myeloid cells that are increased in states of cancer, inflammation and infection. In malignant states, MDSC are induced by tumor secreted growth factors. MDSC play an important part in suppression of host immune responses through several mechanisms such as production of arginase 1, release of reactive oxygen species and nitric oxide and secretion of immune-suppressive cytokines. This leads to a permissive immune environment necessary for the growth of malignant cells. MDSC may also contribute to angiogenesis and tumor invasion. This review focuses on currently available strategies to inhibit MDSC in the treatment of cancer.
              Article 0 comments Cited 124 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ecancermedicalscience
                Journal ID (iso-abbrev): Ecancermedicalscience
                Journal ID (publisher-id): ecancermedicalscience
                Title: ecancermedicalscience
                Publisher: Cancer Intelligence
                ISSN (Electronic): 1754-6605
                Publication date Collection: 2018
                Publication date (Electronic): 11 April 2018
                Volume: 12
                Electronic Location Identifier: 824
                Affiliations
                [1 ]Anticancer Fund, Brussels, Strombeek-Bever 1853, Belgium
                [2 ]The George Pantziarka TP53 Trust, London KT1 2JP, UK
                [3 ]GlobalCures Inc., Newton, MA 02459, USA
                [4 ]Emory University School of Medicine, Atlanta, GA 30322, USA
                Author notes
                Correspondence to: Pan Pantziarka. anticancer.org.uk@ 123456gmail.com
                Article
                Publisher ID: can-12-824
                DOI: 10.3332/ecancer.2018.824
                PMC ID: 5931815
                PubMed ID: 29743944
                SO-VID: 5d8b7393-5b34-4d6d-947b-575f95bf0abc
                Copyright © © the authors; licensee ecancermedicalscience.
                License:

                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
                Date received : 22 January 2018
                Categories
                Subject: Clinical Study

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: drug repurposing,pde5 inhibitors,sildenafil,tadalafil,verdenafil,immunotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: drug repurposing, pde5 inhibitors, sildenafil, tadalafil, verdenafil, immunotherapy

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