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      High dose gabapentin does not alter tumor growth in mice but reduces arginase activity and increases superoxide dismutase, IL-6 and MCP-1 levels in Ehrlich ascites

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          Abstract

          Objectives

          The purpose of this study was to evaluate the effect of gabapentin on Ehrlich tumor growth in Swiss mice, a highly aggressive and inflammatory tumor model. Mice were grouped into sets of 5 animals and treated from days 2 to 8 with gabapentin 30 mg/kg body weight (G30) or 100 mg/kg body weight (G100), or normal sterile saline (control).

          Results

          The mice were euthanized on day 10. Tumor growth, tumoricidal agents and inflammatory cytokines levels were assessed. At day 10, G30 and G100 mice gained weight, but there were no differences in tumor cell count or in ascites volume. In G100, there was a reduction in arginase and an increase in SOD activities. There was an increase in IL-6 and MCP-1 levels, especially in G100, but no alterations in TNF-α. There was no direct evidence of tumor induction by gabapentin. However, the findings suggest that its use modulates immune response to a more effector and less deleterious profile, with increase in activity of anti-oxidant enzymes and in cytokines that favor activation of macrophages, which could improve the general status of the tumor host.

          Electronic supplementary material

          The online version of this article (10.1186/s13104-019-4103-9) contains supplementary material, which is available to authorized users.

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          Most cited references22

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          Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes.

          Stimulating the effector functions of tumor-infiltrating T lymphocytes (TIL) in primary and metastatic tumors could improve active and adoptive T-cell therapies for cancer. Abnormal glycolysis, high lactic acid production, proton accumulation, and a reversed intra-extracellular pH gradient are thought to help render tumor microenvironments hostile to roving immune cells. However, there is little knowledge about how acidic microenvironments affect T-cell immunity. Here, we report that lowering the environmental pH to values that characterize tumor masses (pH 6-6.5) was sufficient to establish an anergic state in human and mouse tumor-specific CD8(+) T lymphocytes. This state was characterized by impairment of cytolytic activity and cytokine secretion, reduced expression of IL-2Rα (CD25) and T-cell receptors (TCR), and diminished activation of STAT5 and extracellular signal-regulated kinase (ERK) after TCR activation. In contrast, buffering pH at physiologic values completely restored all these metrics of T-cell function. Systemic treatment of B16-OVA-bearing mice with proton pump inhibitors (PPI) significantly increased the therapeutic efficacy of both active and adoptive immunotherapy. Our findings show that acidification of the tumor microenvironment acts as mechanism of immune escape. Furthermore, they illustrate the potential of PPIs to safely correct T-cell dysfunction and improve the efficacy of T-cell-based cancer treatments. ©2012 AACR
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            A validation study of the WHO method for cancer pain relief.

            The method for cancer pain relief proposed by the World Health Organization (WHO) consists of guidelines for a three-step treatment, from non-opioids to weak and then strong opioids, according to need. Adjuvant drugs can be added to each step. This report presents the 2-year experience of the WHO Collaborating Centre at the National Cancer Institute of Milan in the use of this method. This retrospective study shows that a correct use of the analgesic ladder can reduce pain to a third of its initial intensity. The use of non-opioids had an average duration of 19.2 days; in 52% of the cases treatment was discontinued due to inefficacy and in 42%, to side effects. Weak opioids were administered on an average for 28.0 days. A shift to Strong opioids was made in 92% of the cases due to inefficacy and in 8% because of side effects. Treatment with strong opioids lasted for an average of 46.6 days and can be considered the mainstay of cancer pain therapy. Performance status was not altered considerably during the study and hours of sleep were doubled. The analgesic ladder proved efficacious in 71% of the cases. Neurolytic procedures had to be used in 29%. The authors conclude that analgesics, as proposed by WHO, are the most suitable treatment arm in controlling pain in palliative treatment for advanced cancer patients. Lack of availability or underuse of opioids constitute the real obstacle to the application of this method.
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              Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy

              The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system, and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions. This metabolic reprogramming also plays a significant role in suppressing the immune attack on the tumor cells and in resistance to therapies. Thus, the metabolic cooperation and competition among the different TME components besides the inherent alterations in the tumor cells arising out of genetic as well as epigenetic changes supports growth, metastasis, and therapeutic resistance. This review focuses on the metabolic remodeling achieved through an active cooperation and competition among the three principal components of the TME—the tumor cells, the T cells, and the cancer-associated fibroblasts while discussing about the current strategies that target metabolism of TME components. Further, we will also consider the probable therapeutic opportunities targeting the various metabolic pathways as well as the signaling molecules/transcription factors regulating them for the development of novel treatment strategies for cancer.
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                Author and article information

                Contributors
                pliniocunhaleal@hotmail.com
                edcrmoura@yahoo.com.br
                rachelcossetti@gmail.com
                john_nyramos@yahoo.com.br
                izabogea@uol.com.br
                brunodpr@hotmail.com
                andre_amvale@hotmail.com
                apsazevedo@yahoo.com.br
                nascimentofrf@yahoo.com.br
                rsakata@unifesp.br
                Journal
                BMC Res Notes
                BMC Res Notes
                BMC Research Notes
                BioMed Central (London )
                1756-0500
                25 January 2019
                25 January 2019
                2019
                : 12
                : 59
                Affiliations
                [1 ]ISNI 0000 0001 2165 7632, GRID grid.411204.2, Federal University of Maranhão, ; São Luís, MA Brazil
                [2 ]ISNI 0000 0001 0514 7202, GRID grid.411249.b, Federal University of São Paulo, ; São Paulo, SP Brazil
                [3 ]Rua das Boninas, Bloco 2, apartment 1202, condomínio Ile Saint Louis, São Luís, MA 65077-552 Brazil
                Article
                4103
                10.1186/s13104-019-4103-9
                6347815
                30683148
                e5c46cb4-fdd0-46fb-875c-ffd6b17cc86d
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 3 October 2018
                : 19 January 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: grant no 305608/2015-0
                Award Recipient :
                Funded by: Fundação de Amparo à Pesquisa do Estado do Maranhão
                Award ID: grant no 01354/16
                Award ID: grant no BD-01310/15
                Award Recipient :
                Funded by: Fundação de Amparo à Pesquisa do Estado do Maranhão
                Award ID: grant no 00572/14
                Award Recipient :
                Categories
                Research Note
                Custom metadata
                © The Author(s) 2019

                Medicine
                gabapentin,tumor growth,cytokine,arginine,sod,ehrlich tumor
                Medicine
                gabapentin, tumor growth, cytokine, arginine, sod, ehrlich tumor

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