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      Ketogenic diet in the treatment of cancer – Where do we stand?

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          Abstract

          Background

          Cancer is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of standard anticancer therapies. The ketogenic diet, a high-fat, low-carbohydrate diet with adequate amounts of protein, appears to sensitize most cancers to standard treatment by exploiting the reprogramed metabolism of cancer cells, making the diet a promising candidate as an adjuvant cancer therapy.

          Scope of review

          To critically evaluate available preclinical and clinical evidence regarding the ketogenic diet in the context of cancer therapy. Furthermore, we highlight important mechanisms that could explain the potential antitumor effects of the ketogenic diet.

          Major conclusions

          The ketogenic diet probably creates an unfavorable metabolic environment for cancer cells and thus can be regarded as a promising adjuvant as a patient-specific multifactorial therapy. The majority of preclinical and several clinical studies argue for the use of the ketogenic diet in combination with standard therapies based on its potential to enhance the antitumor effects of classic chemo- and radiotherapy, its overall good safety and tolerability and increase in quality of life. However, to further elucidate the mechanisms of the ketogenic diet as a therapy and evaluate its application in clinical practice, more molecular studies as well as uniformly controlled clinical trials are needed.

          Graphical abstract

          Highlights

          • Ketogenic diets (KDs) can enhance the efficacy of classical antitumor therapies.

          • Effect of KDs on proliferation is tumor type dependent.

          • Application of KDs to cancer patients is generally well tolerated.

          • Low-carbohydrate and KDs increase quality of life of cancer patients.

          • More standardized studies are needed before KDs can be advised for cancer patients.

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          Most cited references160

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Inflammation and cancer: advances and new agents.

            Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response.
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              Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells.

              In this study, we explore the hypothesis that enhanced production of lactate by tumor cells, because of high glycolytic activity, results in inhibition of host immune response to tumor cells. Lactate dehydrogenase-A (LDH-A), responsible for conversion of pyruvate to lactate, is highly expressed in tumor cells. Lentiviral vector-mediated LDH-A short hairpin RNA knockdown Pan02 pancreatic cancer cells injected in C57BL/6 mice developed smaller tumors than mice injected with Pan02 cells. A decrease occurred in the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying LDH-A-depleted tumors. NK cells from LDH-A-depleted tumors had improved cytolytic function. Exogenous lactate increased the frequency of MDSCs generated from mouse bone marrow cells with GM-CSF and IL-6 in vitro. Lactate pretreatment of NK cells in vitro inhibited cytolytic function of both human and mouse NK cells. This reduction of NK cytotoxic activity was accompanied by lower expression of perforin and granzyme in NK cells. The expression of NKp46 was decreased in lactate-treated NK cells. These studies strongly suggest that tumor-derived lactate inhibits NK cell function via direct inhibition of cytolytic function as well as indirectly by increasing the numbers of MDSCs that inhibit NK cytotoxicity. Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                27 July 2019
                March 2020
                27 July 2019
                : 33
                : 102-121
                Affiliations
                [1]Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Müllner Hauptstraße 48, 5020, Salzburg, Austria
                Author notes
                []Corresponding author. b.kofler@ 123456salk.at
                Article
                S2212-8778(19)30427-2
                10.1016/j.molmet.2019.06.026
                7056920
                31399389
                ecca37cf-c9e9-4d99-b5d8-0e6b3902add4
                © 2019 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 1 May 2019
                : 17 June 2019
                : 28 June 2019
                Categories
                Article

                ketogenic diet,tumorigenesis,tumor metabolism,adjuvant cancer therapy

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