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

Marek Samec; Alena Liskova; Lenka Koklesova; Samson Mathews Samuel; Kevin Zhai; Constanze Buhrmann; Elizabeth Varghese; Mariam Abotaleb; Tawar Qaradakhi; Anthony Zulli; Martin Kello; Jan Mojzis; Pavol Zubor; Taeg Kyu Kwon; Mehdi Shakibaei; Dietrich Büsselberg; Gustavo R Sarria; Olga Golubnitschaja; Peter Kubatka

doi:10.1007/s13167-020-00217-y

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

EPMA J. 2020 Jul 30;11(3):377-398. doi: 10.1007/s13167-020-00217-y. eCollection 2020 Sep.

Authors

Marek Samec¹, Alena Liskova¹, Lenka Koklesova¹, Samson Mathews Samuel², Kevin Zhai², Constanze Buhrmann³, Elizabeth Varghese², Mariam Abotaleb², Tawar Qaradakhi⁴, Anthony Zulli⁴, Martin Kello⁵, Jan Mojzis⁵, Pavol Zubor^{6

7}, Taeg Kyu Kwon⁸, Mehdi Shakibaei³, Dietrich Büsselberg², Gustavo R Sarria⁹, Olga Golubnitschaja¹⁰, Peter Kubatka¹¹

Affiliations

¹ Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia.
² Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar.
³ Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany.
⁴ Institute for Health and Sport, Victoria University, Melbourne, VIC 3011 Australia.
⁵ Department of Pharmacology, Faculty of Medicine, P. J. Šafarik University, 040 11 Košice, Slovakia.
⁶ Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway.
⁷ OBGY Health & Care, Ltd., 01001 Zilina, Slovak Republic.
⁸ 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 Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia.

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.

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

Publication types

Review