BACKGROUND: Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. AIM OF REVIEW: We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). KEY SCIENTIFIC CONCEPTS OF REVIEW: The working hypothesis of the manuscript proposes HIF-1α - the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation.

Chair of Vegetative Anatomy Institute of Anatomy Faculty of Medicine Ludwig Maximilians University Munich Pettenkoferstr 11 D 80336 Munich Germany

Clinic of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Anatomy Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Animal Physiology Institute of Biology and Ecology Faculty of Science P J Safarik University 04001 Kosice Slovakia

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 165 00 Prague Czech Republic

Department of Histology and Embryology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Natural Drugs Faculty of Pharmacy Masaryk University 61242 Brno Czech Republic

Department of Pathological Physiology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Physiology and Biophysics Weill Cornell Medicine in Qatar Education City Qatar Foundation 24144 Doha Qatar

Department of Physiology and Pharmacology Vittorio Erspamer Sapienza University P le Aldo Moro 5 00185 Rome Italy

Museum of Literature in Moravia Klášter 1 66461 Rajhrad Czech Republic

Predictive Preventive and Personalised Medicine Department of Radiation Oncology University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn 53127 Bonn Germany

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