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      Flavonoids against the Warburg phenotype—concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism

      review-article
      1 , 1 , 1 , 2 , 2 , 3 , 2 , 2 , 4 , 4 , 5 , 5 , 6 , 7 , 8 , 3 , 2 , 9 , 10 , , 11 ,
      The EPMA Journal
      Springer International Publishing
      Predictive preventive personalised medicine (PPPM / 3PM), Cancer, Warburg phenotype, Flavonoids, Anticancer effect, Cell metabolism, Co-morbidities, Malignancy, Disease manifestation, Age, Patient stratification, Aggressive metastatic disease, Multi-omics, Biomarker patterns, Liquid biopsy, Modifiable risk factors, Risk assessment, Microcirculation, Systemic hypoxia, Ischemic lesions, Prognosis, Individualised patient profiles, Treatment algorithms, Liver malignancy, Triple-negative breast cancer, Prostate cancer, Pregnancy, Chemoresistance, Radioresistance, Glucose metabolism, Oxidative phosphorylation, Proliferation, Metabolic reprogramming, Positron emission tomography, Magnetic resonance spectroscopy, Tumour imaging, FDG-PET, Glucose intake, PET-CT, Individual outcome, Palliative medicine, Polyphenols, Glycolysis, Carcinogenesis, Prognostic markers, Aerobic glycolysis, Glycolytic inhibitors, Pleiotropic activity, HIF-1

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          Abstract

          The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the ‘Warburg reprogramming’ of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of ‘anti-Warburg’ effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted ‘anti-Warburg’ measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted ‘anti-Warburg’ measures in the context of predictive, preventive and personalised medicine.

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          Most cited references87

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          The Acidic Tumor Microenvironment as a Driver of Cancer

          Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.
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            Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

            The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.
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              PKM2, cancer metabolism, and the road ahead.

              A major metabolic aberration associated with cancer is a change in glucose metabolism. Isoform selection of the glycolytic enzyme pyruvate kinase has been implicated in the metabolic phenotype of cancer cells, and specific pyruvate kinase isoforms have been suggested to support divergent energetic and biosynthetic requirements of cells in tumors and normal tissues. PKM2 isoform expression has been closely linked to embryogenesis, tissue repair, and cancer. In contrast, forced expression of the PKM1 isoform has been associated with reduced tumor cell proliferation. Here, we discuss the role that PKM2 plays in cells and provide a historical perspective for how the study of PKM2 has contributed to understanding cancer metabolism. We also review recent studies that raise important questions with regard to the role of PKM2 in both normal and cancer cell metabolism.
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                Author and article information

                Contributors
                marek.samec@gmail.com
                liskova80@uniba.sk
                koklesova.lenka@gmail.com
                sms2016@qatar-med.cornell.edu
                kez4003@qatar-med.cornell.edu
                constanze.buhrmann@med.uni-muenchen.de
                elv2007@qatar-med.cornell.edu
                mariam.abotaleb@aucegypt.edu
                tawar.qaradakhi@live.vu.edu.au
                Anthony.Zulli@vu.edu.au
                martin.kello@yahoo.com
                jan.mojzis@upjs.sk
                pavzub@ous-hf.no
                kwontk@dsmc.or.kr
                mehdi.shakibaei@med.uni-muenchen.de
                dib2015@qatar-med.cornell.edu
                olga.golubnitschaja@ukbonn.de
                peter.kubatka@uniba.sk
                Journal
                EPMA J
                EPMA J
                The EPMA Journal
                Springer International Publishing (Cham )
                1878-5077
                1878-5085
                30 July 2020
                30 July 2020
                September 2020
                : 11
                : 3
                : 377-398
                Affiliations
                [1 ]GRID grid.7634.6, ISNI 0000000109409708, Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, , Comenius University in Bratislava, ; 03601 Martin, Slovakia
                [2 ]GRID grid.418818.c, ISNI 0000 0001 0516 2170, Department of Physiology and Biophysics, , Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, ; 24144, Doha, Qatar
                [3 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, , Ludwig-Maximilian-University Munich, ; 80336 Munich, Germany
                [4 ]GRID grid.1019.9, ISNI 0000 0001 0396 9544, Institute for Health and Sport, , Victoria University, ; Melbourne, VIC 3011 Australia
                [5 ]GRID grid.11175.33, ISNI 0000 0004 0576 0391, Department of Pharmacology, Faculty of Medicine, , P. J. Šafarik University, ; 040 11 Košice, Slovakia
                [6 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Gynecologic Oncology, Norwegian Radium Hospital, , Oslo University Hospital, ; 0379 Oslo, Norway
                [7 ]OBGY Health & Care, Ltd., 01001 Zilina, Slovak Republic
                [8 ]GRID grid.412091.f, ISNI 0000 0001 0669 3109, Department of Immunology and School of Medicine, , Keimyung University, ; Dalseo-Gu, Daegu, 426 01 South Korea
                [9 ]Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
                [10 ]Predictive, Preventive Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
                [11 ]GRID grid.7634.6, ISNI 0000000109409708, Department of Medical Biology, Jessenius Faculty of Medicine, , Comenius University in Bratislava, ; 036 01 Martin, Slovakia
                Article
                217
                10.1007/s13167-020-00217-y
                7429635
                32843908
                afb06329-79bf-4262-b6d2-f8d77886bbbc
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 June 2020
                : 30 June 2020
                Funding
                Funded by: Rheinische Friedrich-Wilhelms-Universität Bonn (1040)
                Categories
                Review
                Custom metadata
                © European Association for Predictive, Preventive and Personalised Medicine (EPMA) 2020

                Molecular medicine
                predictive preventive personalised medicine (pppm / 3pm),cancer,warburg phenotype,flavonoids,anticancer effect,cell metabolism,co-morbidities,malignancy,disease manifestation,age,patient stratification,aggressive metastatic disease,multi-omics,biomarker patterns,liquid biopsy,modifiable risk factors,risk assessment,microcirculation,systemic hypoxia,ischemic lesions,prognosis,individualised patient profiles,treatment algorithms,liver malignancy,triple-negative breast cancer,prostate cancer,pregnancy,chemoresistance,radioresistance,glucose metabolism,oxidative phosphorylation,proliferation,metabolic reprogramming,positron emission tomography,magnetic resonance spectroscopy,tumour imaging,fdg-pet,glucose intake,pet-ct,individual outcome,palliative medicine,polyphenols,glycolysis,carcinogenesis,prognostic markers,aerobic glycolysis,glycolytic inhibitors,pleiotropic activity,hif-1

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