Natural Compounds that Slow Glycolysis in Cancers – Part 1

Dr. Kevin Conners

As a young scientist in the 1920’s, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect) that earned him a Nobel Prize. Glycolysis is the metabolic pathway where cells take glucose to produce energy for cell function and replication [1].

The alternative cancer world has long seen this fact as a therapeutic strategy to help block cancer’s fuel source. In this series of articles, we will explore the latest scientific data that support various natural compounds effect on glycolysis to inhibit the Warburg effect [2].


Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger the Warburg effect. Thus, how to inhibit HIF-1-dependent, Warburg effect, to assist the cancer therapy is becoming a hot issue in cancer research. While the pharmaceutical industry scrambles to produce a patentable drug, research is backing natural substances that we can use now.

Here are a few details about HIF-1. It up regulates the glucose transporters (GLUT) that increase the amount of glucose getting into the cell, a bad thing for those with cancer as it fuels the fire. It induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase, so glucose is more readily used as an energy source. If there exists natural compounds to help regulate these glycolysis-signaling pathways, we may help more people with cancer [3,4].

First let’s explore nutrients that may regulate the glucose transporters that are related to glycolysis. Many natural compounds affect expression of glucose transporters (especially GLUT1 and GLUT4) indirectly. Flavones, polyphenols, and alkaloids are interesting bioactive anticancer molecules isolated from plants, as several of them have been repeatedly reported to control glucose transporter activity in different cancer cell models.

Flavones are plant-derived compounds that are commonly consumed in the diet as flavonoids. These are present in fruits, vegetables, tea, red wine, dark chocolate, and herbs such as ginkgo biloba, and milk thistle. Polyphenols give fruits, berries, and vegetables their vibrant colors, and contribute to the bitterness, astringency, flavor, and aroma. They are found in a wide variety of foods, herbs, berries, fruits, and spices.

These compounds have various names (Fisetin, myricetin, quercetin, apigenin, genistein, cyanidin, daidzein, hesperetin, naringenin, and catechin) with distinct properties. As a matter of fact, comparative studies indicated that these compounds do not exhibit the same mode of action as they bind different domains of GLUT1 to slow glucose transmission. Genistein (an isoflavone found in soy) binds the transporter on the external face whereas quercetin (a flavonoid found in many fruits and vegetables) interacts with the internal face [7]. It’s as if they play different positions on the team’s defensive line, blocking the opposition at alternate angles.

Numerous research articles have been written on the benefits of each of these but it may be the synergy between them, as they are naturally found in food sources that really make them winners. Together, they are well-known inhibitors of glucose uptake in human cells making them beneficial for cancer patients but also diabetics and just about any other inflammatory disorder [4].

There are also genetic mutations that influence aerobic glycolysis that curcumin (the active form of the Indian spice turmeric) has proven to reverse [6]. Another natural isoflavinoid, 4-O-methyl alpinumisoflavone, isolated from the tropical rainforest tree, Lonchocarpus glabrescens, could inhibit HIF-1 activation and hypoxic induction of HIF-1 target genes (CDKN1A, GLUT-1, and vascular endothelial growth factor (VEGF)) [9].

Also, long chained fatty acid derivatives extracted from Graviola have recently shown multiple anticancer activities on pancreatic cancer cell models. Torres et al. highlighted the ability of this compound to inhibit glucose uptake, and it has strong ability to reduce the expression levels of GLUT1 and GLUT4, HKII, and LDH-A pathways, making it a great player against most cancers [8].

I believe that getting one’s nutrition from one’s food is the best approach to care whenever possible. We can get plenty of GLUT blocking players from organic vegetables, fruits, herbs and spices. It is best to eat them as near to the way God made them, organic, fresh, and whole. While juicing has advantages in predigesting, it removes some of its value. Maybe blending is a better option. Other nutrients mentioned, like curcumin and Graviola, might better be consumed as a supplement.

  1. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
  2. G. V. Heiden, L. C. Cantley, and C. B. Thompson, “Understanding the warburg effect: the metabolic requirements of cell proliferation,” Science, vol. 324, no. 5930, pp. 1029–1033, 2009.
  3. Chen, J. Xie, Z. Jiang, B. Wang, Y. Wang, and X. Hu, “Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2,” Oncogene, vol. 30, no. 42, pp. 4297–4306, 2011.
  4. B. Park, “Flavonoids are potential inhibitors of glucose uptake in U937 cells,” Biochemical and Biophysical Research Communications, vol. 260, no. 2, pp. 568–574, 1999.
  5. Nomura, T. Takahashi, N. Nagata et al., “Inhibitory mechanisms of flavonoids on insulin-stimulated glucose uptake in MC3T3-G2/PA6 adipose cells,” Biological and Pharmaceutical Bulletin, vol. 31, no. 7, pp. 1403–1409, 2008.
  6. A. Vaughan, R. Garcia-Smith, J. Dorsey, J. K. Griffith, M. Bisoffi, and K. A. Trujillo, “Tumor necrosis factor alpha induces Warburg-like metabolism and is reversed by anti-inflammatory curcumin in breast epithelial cells,” International Journal of Cancer, vol. 133, no. 10, pp. 2504–2510, 2013.
  7. Pérez, P. Ojeda, L. Ojeda et al., “Hexose transporter GLUT1 harbors several distinct regulatory binding sites for flavones and tyrphostins,” Biochemistry, vol. 50, no. 41, pp. 8834–8845, 2011.
  8. P. Torres, S. Rachagani, V. Purohit et al., “Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism,” Cancer Letters, vol. 323, no. 1, pp. 29–40, 2012.