Phytochemicals as Regulators of Tumor Glycolysis and Hypoxia Signaling Pathways: Evidence from In Vitro Studies

Abstract

The full understanding of the complex nature of cancer still faces many challenges, as cancers arise not as a result of a single target disruption but rather involving successive genetic and epigenetic alterations leading to multiple altered metabolic pathways. In this light, the need for a multitargeted, safe and effective therapy becomes essential. Substantial experimental evidence upholds the potential of plant-derived compounds to interfere in several important pathways, such as tumor glycolysis and the upstream regulating mechanisms of hypoxia. Herein, we present a comprehensive overview of the natural compounds which demonstrated, in vitro studies, an effective anticancer activity by affecting key regulators of the glycolytic pathway such as glucose transporters, hexokinases, phosphofructokinase, pyruvate kinase or lactate dehydrogenase. Moreover, we assessed how phytochemicals could interfere in HIF-1 synthesis, stabilization, accumulation, and transactivation, emphasizing PI3K/Akt/mTOR and MAPK/ERK pathways as important signaling cascades in HIF-1 activation. Special consideration was given to cell culture-based metabolomics as one of the most sensitive, accurate, and comprising approaches for understanding the response of cancer cell metabolome to phytochemicals.

Keywords: HIF-1 signaling pathway; Warburg effect; metabolomics; phytochemicals; tumor glycolysis; tumor hypoxia.

Figure 1

Phytochemicals targeting glycolysis and hypoxia signaling pathways: classification, main representants, and chemical structures (the chemical structure belongs to the compound marked in bold).

Figure 2

Simplified scheme of the energetic metabolism in cancer cells. Aerobic Glycolysis, Pentose Pyruvate Pathway, and TCA cycle. Natural compounds which inhibit the glycolytic pathway according to in vitro studies (the ligand-binding screening studies without in vitro testing were excluded): 1. Apigenin, 2. Berberine, 3. Bergapten, 4. Chrysin, 5. Costunolide, 6. Daidzein, 7. Deguelin, 8. Dioscin, 9. Epigallocatechin, 10. Epigallocatechin gallate, 11. Galloflavin, 12. Genistein, 13. Gliotoxin, 14. Glucopiericidin A, 15. Kaempferol, 16. Oleanolic acid, 17. Oroxylin A, 18. Phloretin, 19. Pseurotin A, 20. Prosapogenin A, 21. Quercetin, 22. Resveratrol, 23. Scutellarin, 24. Silybin, 25. Shikonin, 26. Sulforaphane, 27. Wogonin, 28. Worenine, 29. Xanthohumol. The red-colored enzymes represent key regulators of the glycolytic pathway.

Figure 3

HIF-1α signaling pathways and their natural regulators. A. HIF-1α translation via PI3K/AKT/mTOR and RAS/MEK/ERK pathways B. ERK regulation of the HIF transcription regulatory complex. C. Degradation of HIF-1α via pVHL mediated ubiquitination (in the presence of oxygen) and via p53/Mdm2 mediated ubiquitination (independent of oxygen). In normoxia, FIH-1 hydroxylates HIF-1α and impedes its transactivation. Natural compounds which inhibit the HIF-1 pathway: 1. Apigenin, 2. Biochanin A, 3. Berberine, 4. Baicalein, 5. Curcumin, 6. Chrysin, 7. Chlorogenic acid, 8. Cryptotanshinone, 9. Deguelin, 10. Dictamnine, 11. Epigallocatechin-3-gallate (EGCG), 12. EGCG and green tea extract (GTE), 13. Galangin, 14. Gambogic acid, 15. Genistein, 16. Kaempferol, 17. Licochalcone A, 18. Luteolin, 19. Magnolol, 20. Myricetin, 21. Oridonin, 22. Oroxylin A, 23. Quercetin, 24. Resveratrol, and 25. Wogonin.