Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism.

Biomedical Centre Martin Jessenius Faculty of Medicine in Martin Comenius University in Bratislava Mala Hora 4D 03601 Martin Slovakia

Clinic of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Biology Faculty of Science Islamic Azad University Science and Research Branch 1477893855 Tehran Iran

Department of Food Hygiene and Quality Control Division of Epidemiology Faculty of Veterinary Medicine University of Tehran 1419963114 Tehran Iran

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Natural Drugs Faculty of Pharmacy Masaryk University Palackého třída 1946 1 61200 Brno Czech Republic

Department of Pathology St Elizabeth Cancer Institute Hospital 81250 Bratislava Slovakia

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

Department of Physiology and Pharmacology Vittorio Erspamer Faculty of Pharmacy and Medicine Sapienza University 00185 Rome Italy

Faculty of Engineering and Natural Sciences Sabanci University Orta Mahalle Üniversite Caddesi No 27 Orhanlı Tuzla 34956 Istanbul Turkey

Musculoskeletal Research Group and Tumor Biology Chair of Vegetative Anatomy Institute of Anatomy Faculty of Medicine Ludwig Maximilian University Munich D 80336 Munich Germany

Sabanci University Nanotechnology Research and Application Center Tuzla 34956 Istanbul Turkey

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