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      New Aspects of an Old Drug – Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells

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          Abstract

          Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 ( GLUT1), lactate dehydrogenase A ( LDHA), and monocarboxylate transporter 1 ( MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor α-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies.

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          Most cited references46

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          The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes.

          Cells from some tumors use an altered metabolic pattern compared with that of normal differentiated adult cells in the body. Tumor cells take up much more glucose and mainly process it through aerobic glycolysis, producing large quantities of secreted lactate with a lower use of oxidative phosphorylation that would generate more adenosine triphosphate (ATP), water, and carbon dioxide. This is the Warburg effect, which provides substrates for cell growth and division and free energy (ATP) from enhanced glucose use. This metabolic switch places the emphasis on producing intermediates for cell growth and division, and it is regulated by both oncogenes and tumor suppressor genes in a number of key cancer-producing pathways. Blocking these metabolic pathways or restoring these altered pathways could lead to a new approach in cancer treatments.
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            p53 regulates mitochondrial respiration.

            The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
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              Lactate: a metabolic key player in cancer.

              Increased glucose uptake and accumulation of lactate, even under normoxic conditions (i.e., aerobic glycolysis or the Warburg Effect), is a common feature of cancer cells. This phenomenon clearly indicates that lactate is not a surrogate of tumor hypoxia. Tumor lactate can predict for metastases and overall survival of patients, as shown by several studies of different entities. Metastasis of tumors is promoted by lactate-induced secretion of hyaluronan by tumor-associated fibroblasts that create a milieu favorable for migration. Lactate itself has been found to induce the migration of cells and cell clusters. Furthermore, radioresistance has been positively correlated with lactate concentrations, suggesting an antioxidative capacity of lactate. Findings on interactions of tumor metabolites with immune cells indicate a contribution of lactate to the immune escape. Furthermore, lactate bridges the gap between high lactate levels in wound healing, chronic inflammation, and cancer development. Tumor cells ensure sufficient oxygen and nutrient supply for proliferation through lactate-induced secretion of VEGF, resulting in the formation of new vessels. In summary, accumulation of lactate in solid tumors is a pivotal and early event in the development of malignancies. The determination of lactate should enter further clinical trials to confirm its relevance in cancer biology. ©2011 AACR
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                9 July 2013
                : 8
                : 7
                : e66987
                Affiliations
                [1 ]Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
                [2 ]Regensburg Centre for Interventional Immunology (RCI), University of Regensburg, Regensburg, Germany
                [3 ]Department of Surgery, University of Regensburg, Regensburg, Germany
                [4 ]Institute of Pathology, University of Regensburg, Regensburg, Germany
                [5 ]Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
                [6 ]Department of Internal Medicine 5, Hematology/Oncology, University of Erlangen, Erlangen, Germany
                [7 ]Department of Neurology, University of Muenster, Muenster, Germany
                [8 ]Department of Neurology, University of Regensburg, Regensburg, Germany
                [9 ]Wilhelm Sander NeuroOncology Unit, University of Regensburg, Regensburg, Germany
                Instituto Nacional de Cardiologia, Mexico
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MK PO EG. Performed the experiments: SL AB WG MR SE IG AS KS KR OG PH KD. Analyzed the data: SL AB WG MR SE IG KS KR OG PH KD. Contributed reagents/materials/analysis tools: AM RA. Wrote the paper: MK PO EG.

                Article
                PONE-D-12-38508
                10.1371/journal.pone.0066987
                3706586
                23874405
                59a63b86-de65-486b-ac3f-5a716fde2dc2
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 6 December 2012
                : 10 May 2013
                Page count
                Pages: 12
                Funding
                This project was supported in part by the Deutsche Forschungsgemeinschaft (Krm-1418/7-1), BayGene, and by intra-mural funding (ReForm-C program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Enzymes
                Metabolism
                Molecular Cell Biology
                Cell Growth
                Gene Expression
                Membranes and Sorting
                Signal Transduction
                Medicine
                Oncology
                Cancer Treatment
                Chemotherapy and Drug Treatment
                Basic Cancer Research

                Uncategorized
                Uncategorized

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