Shared Metabolic Cancer Traits

Almost all cancers share a metabolic phenomenon known as the Warburg Effect in which cancer cells up-reguate the use of sugars for energy and down-regulate the use of the mitochondria, the cell’s main powerhouses, which use oxidative phosphorylation. The reason a ketogenic diet works is it eliminates sugars, thus depriving cancer cells of their main energy source. But, sugar analogues (molecules that mimick sugar) can be used to slow down or inhibit sugar metabolism. Cancer cells also utilize glutamine, an amino acid, for energy as well. This is known as the Q-effect. Metabolic therapy targets both blocking or inhibiting both sugar and glutamine metabolism in cancer cells. Without energy, the cells starve. Thus, the use of the ketogenic diet is emplyed, as it eliminates sugars and produces ketones for fuel, which cancer cells cannot utilize secondary to their damaged mitochondria. Then sugar analogs and glutamine inhibitors are added to further starve the cancer cells of energy. Cancer cells also produce reactive oxygen species (ROS) at higher levels than normal cells. But they also up-regulate antioxidants. Hyperbaric oxygen therapy attempts to push the ROS levels “over the edge” enough to kill the cancer cells while leaving normal cells intact. See the sections on Glutamine inhibition and hyperbaric oxygen therapy for more info on those therapies.

3-Bromopyruvate (3BP)

A3-Bromopyruvate (3BP) is a brominated pyruvate. Pyruvate is the the “end product” of sugar metabolism where it either becomes lactate (in anaerobic conditions) or Acetyl-CoA. 3BP enters cancer cells readily through the monocarboxylate transporters (MCTs) that get increased in cancer cells. Once in the cancer cells 3BP acts in the following ways:

1. Inhibition of glycolysis:

• 3-BP primarily inhibits hexokinase II (HKII), a key glycolytic enzyme that is often overexpressed in cancer cells[1][3].

• It also inhibits other glycolytic enzymes like glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH)[5].

• This disrupts the glycolytic pathway that many cancer cells rely on for energy production.

2. ATP depletion:

• By inhibiting glycolysis and mitochondrial function, 3-BP causes a rapid depletion of cellular ATP levels[1][3][5].

• This energy crisis leads to cancer cell death.

3. Selective uptake by cancer cells:

• 3-BP is preferentially taken up by cancer cells via monocarboxylate transporters (MCTs), which are often overexpressed in tumors[3][5].

• This allows for selective targeting of cancer cells while sparing normal cells.

4. Induction of oxidative stress:

• 3-BP treatment increases levels of reactive oxygen species (ROS) in cancer cells[1][5].

• This oxidative stress can lead to DNA damage and cell death.

5. Mitochondrial effects:

• 3-BP can inhibit mitochondrial complexes I and II, further disrupting energy production[5].

6. Induction of cell death:

• 3-BP can induce cancer cell death through multiple mechanisms, including apoptosis, necroptosis, and autophagy[1][4].

7. Synergy with other therapies:

• 3-BP has shown potential to enhance the effects of other chemotherapeutic agents by increasing their retention in cancer cells[3].

8. Targeting cancer stem cells:

• Some studies suggest 3-BP may be effective against cancer stem cells, potentially reducing tumor recurrence[1].

9. Overcoming drug resistance:

• 3-BP has shown promise in overcoming resistance to other cancer therapies in some cases[2].

The multi-targeted approach of 3-BP, combined with its preferential uptake by cancer cells, makes it a promising candidate for cancer therapy. However, it's important to note that while 3-BP has shown significant potential in preclinical studies, more research is needed to fully establish its efficacy and safety in clinical settings.

Citations:

[1] https://journals.lww.com/sjmm/Fulltext/2017/05010/Targeting_Cancer_Cells_using_3_bromopyruvate_for.3.aspx

[2] https://www.nature.com/articles/s41417-023-00648-5

[3] https://ar.iiarjournals.org/content/33/1/13

[4] https://pubmed.ncbi.nlm.nih.gov/26054380/

[5] https://www.mdpi.com/2073-4409/9/5/1161

[6] https://portlandpress.com/bioscirep/article/36/1/e00299/56385/The-effect-of-3-bromopyruvate-on-human-colorectal

[7] https://www.spandidos-publications.com/10.3892/or.2015.4147

Research

Ko YH, Niedźwiecka K, Casal M, Pedersen PL, Ułaszewski S. 3-Bromopyruvate as a potent anticancer therapy in honor and memory of the late Professor André Goffeau. Yeast. 2019 Apr;36(4):211-221. doi: 10.1002/yea.3367. Epub 2018 Dec 13. PMID: 30462852.

Attia YM, EL-Abhar HS, Marzabani MMA, et al. Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines. BMC Cancer. 2015;15(1):838.

Gandham SK, Talekar M, Singh A, et al. Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis. Int. J. Nanomed. 2015;10:4405–4423.

Ko YH, Smith BL, Wang Y, et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem. Biophys. Res. Commun. 2004;324(1):269–275.

Ko YH, Verhoeven HA, Lee MJ, et al. A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J. Bioenerg. Biomembr. 2012;44(1):163–170.

Sayed SME, Mohamed WG, Seddik M-AH, et al. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chin. J. Cancer. 2014;33(7):356–364.

Mathupala, S. P., Ko, Y. H., & Pedersen, P. L. (2009). Hexokinase-2 bound to mitochondria: Cancer's stygian link to the “Warburg effect” and a pivotal target for effective therapy. *Seminars in Cancer Biology, 19*(1), 17–24. doi:10.1016/j.semcancer.2008.11.006.

Seyfried TN, Yu G, Maroon JC, et al. Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr. Metab. 2017;14(1):19.

Sayed SME. Enhancing anticancer effects, decreasing risks and solving practical problems facing 3-bromopyruvate in clinical oncology: 10 years of research experience. Int. J. Nanomed. 2018;13:4699–4709.

Lis P, Dyląg M, Niedźwiecka K, et al. The HK2 Dependent “Warburg Effect” and Mitochondrial Oxidative Phosphorylation in Cancer: Targets for Effective Therapy with 3-Bromopyruvate. Molecules. 2016;21(12):1730.

Ganapathy-Kanniappan S, Kunjithapatham R, Geschwind J-F. Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting. Anticancer Res. 2012;33(1):13–20.

2-Deoxy-D-Glucose (2-DG)

2-deoxy-D-glucose (2-DG) is a glucose analog that has shown potential as a therapeutic agent for various conditions, particularly cancer and viral infections. Here are the key points about 2-DG:

Structure and Mechanism

• 2-DG is a modified glucose molecule where the 2-hydroxyl group is replaced by hydrogen

• It is taken up by cells through glucose transporters but cannot be fully metabolized

• 2-DG inhibits glycolysis and glucose metabolism by competing with glucose

Effects on Cells

• Inhibits energy production by blocking glycolysis

• Causes ATP depletion in cells

• Induces oxidative stress

• Interferes with N-linked glycosylation

• Can trigger cell death pathways like apoptosis and autophagy

Potential Therapeutic Applications

2-Deoxy-D-glucose (2-DG) specifically targets cancer cells through several mechanisms that exploit the altered glucose metabolism characteristic of many cancer cells:

1. Increased uptake in cancer cells:

Cancer cells typically have higher glucose uptake compared to normal cells due to overexpression of glucose transporters, particularly GLUT1 and GLUT4. 2-DG, being a glucose analog, is transported into cancer cells more readily through these upregulated glucose transporters[1][2].

2. Competitive inhibition of glucose metabolism:

Once inside the cell, 2-DG competes with glucose for phosphorylation by hexokinase, the first enzyme in the glycolysis pathway. This leads to the formation of 2-deoxy-D-glucose-6-phosphate (2-DG-6-P), which cannot be further metabolized[2].

3. Accumulation of 2-DG-6-P:

The accumulation of 2-DG-6-P in cancer cells leads to:

• Inhibition of hexokinase and glucose-6-phosphate isomerase, key enzymes in glycolysis

• Depletion of cellular ATP

• Allosteric inhibition of glycolysis[1][2]

4. Exploitation of the Warburg effect:

Cancer cells often rely heavily on aerobic glycolysis for energy production (the Warburg effect). By inhibiting glycolysis, 2-DG deprives cancer cells of their primary energy source, leading to energetic stress and potentially cell death[1][3].

5. Enhanced effect in hypoxic conditions:

In the hypoxic areas of solid tumors, cells are even more dependent on glycolysis. 2-DG is particularly effective in these regions, where cancer cells cannot easily switch to alternative energy sources[4].

6. Induction of oxidative stress:

2-DG treatment increases reactive oxygen species (ROS) generation in cancer cells, leading to oxidative stress and potentially triggering cell death pathways[2].

7. Inhibition of N-linked glycosylation:

2-DG interferes with N-linked glycosylation, a process important for proper protein folding and function. This can lead to endoplasmic reticulum stress and activation of the unfolded protein response in cancer cells[1].

8. Targeting cancer stem cells:

Some studies suggest that 2-DG can specifically target cancer stem cells, which are often resistant to conventional therapies. 2-DG has been shown to decrease the proportion of cells with cancer stem cell phenotype in certain aggressive cancer types[4].

9. Synergistic effects with other therapies:

2-DG can sensitize cancer cells to other treatments like chemotherapy and radiotherapy, potentially by inhibiting DNA repair mechanisms and enhancing cellular stress[2][3].

By exploiting these multiple mechanisms, 2-DG can preferentially target cancer cells while having less impact on normal cells that are not as dependent on glycolysis and have more flexible metabolism. However, it's important to note that while 2-DG shows promise in preclinical studies, its clinical application has been limited by toxicity at effective doses and challenges in achieving sufficient selectivity for cancer cells in vivo[2][3].

Safety and Side Effects

• Generally well-tolerated at therapeutic doses

• Common side effects include mild hyperglycemia, fatigue, and nausea

• Potential for QTc prolongation at very high doses

Citations:

[1] https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.940129/full

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC8653447/

[3] https://pmc.ncbi.nlm.nih.gov/articles/PMC9041304/

[4] https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.899633/full

[5] https://en.wikipedia.org/wiki/2-Deoxy-D-glucose

[6] https://pmc.ncbi.nlm.nih.gov/articles/PMC6982256/

[7] https://www.medrxiv.org/content/10.1101/2021.10.08.21258621v1.full

[8] https://www.nature.com/articles/s41598-019-39789-9