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:
[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
[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
NEW SUGAR ANALOGUE CONJUGATE MOLECULE FOR GLIOBLASTOMA VIA INTRANASAL DELIVERY
A new molecule called NEO218 has been developed for the delivery of two cancer therapies combining 3-Bromopyruvate with Pyrillic Acid. 3-Bromopyruvate (3BP) acts to weaken and kill cancer cells by stopping or slowing glycolysis, the use of sugar molecules, in cancer cells. Cancer cells exhibit the use of sugar as their primary fuel source. By blocking this, it starves cancer cells of energy while having no impact on normal cells. The problem with 3BP is its delivery to cancer cells. It is rapidly broken down in the body. Thus, there is ongoing experimentation with placing 3BP in “carrier” entities such as cyclodextrins and liposomes.
Perillyl Alcohol (POH) has been shown to have anticancer properties. However, oral administration is not well tolerated. It acts against cancer in the following ways:
Induces endoplasmic reticulum (ER) stress, upregulating pro-apoptotic proteins like CHOP and activating transcription factor.
Inhibits Ras signaling and mTOR pathways, disrupting tumor survival and angiogenesis.
Reduces invasiveness of glioma cells by modulating matrix metalloproteinases.
Synergizes with other agents (e.g., temozolomide) to overcome chemotherapy resistance.
Oral administration of POH has shown little success in anticancer activity. However, intranasal delivery has shown:
Phase I/II Trials for Glioblastoma (GBM):
Recurrent GBM patients received intranasal POH (NEO100) at doses up to 1,152 mg/day. Treatment was well-tolerated, with no severe adverse events.
Survival Outcomes:
33% progression-free survival at 6 months .
55% overall survival at 12 months (OS-12), with median OS of 15 months.
IDH1-mutant patients showed exceptional survival (>24 months).
In Vitro Studies
NEO218, the conjugate of 3-bromopyruvate (3-BP) and perillyl alcohol (POH), has been tested against various cancer cell lines.
NEO218 induces rapid necrosis in tumor cells by:
Pyruvylating all four cysteine residues of the glycolytic enzyme GAPDH, thereby shutting down its activity.
Severely lowering cellular ATP to below life-sustaining levels.
Unlike 3-BP, NEO218’s cytotoxicity is independent of monocarboxylate transporter 1 (MCT-1), meaning it can kill both MCT-1-positive and -negative tumor cells.
Supplemental antioxidants (NAC, GSH) can block the cytotoxic activity of both NEO218 and 3-BP, but supplemental pyruvate only protects against 3-BP, not NEO218.
NEO218 overcomes resistance mechanisms that limit 3-BP’s efficacy: tumor cells that develop resistance to 3-BP (by losing MCT-1 expression) remain sensitive to NEO218.
In Vivo (Animal) Studies
Preclinical animal studies have shown that NEO218 has potent anticancer activity.
In mouse xenograft models (e.g., HCT116 colon carcinoma), NEO218 significantly suppressed tumor growth.
The conjugate was well-tolerated in animals, with no observed systemic toxicity at therapeutic doses.
These studies demonstrated that NEO218 could overcome limitations of 3-BP, such as transporter dependence and rapid resistance development, and provided robust tumor suppression in vivo.
NEO 212: Temozolomide combined with Perillyl Alcohol
While this section has been primarily focused on specific metabolic therapies, in researching NEO218 I discovered NEO212. Clinical trials of NEO218 have been limited. But phase I clinical trials of NEO 212, a combination of perillyl alcohol with Temozolomide (the primary chemotherapeutic therapy for gliablastoma) have shown much promise.
Neo 212 is a novel, patented small-molecule anticancer agent created by covalently conjugating temozolomide (TMZ)-the standard-of-care alkylating chemotherapy for malignant gliomas-with perillyl alcohol (POH), a naturally occurring monoterpene with anticancer properties. This conjugation produces a stable, orally bioavailable compound designed to overcome several key limitations of TMZ, particularly in the treatment of brain cancers.
Key Features and Mechanism
NEO212 preferentially concentrates in brain tumor tissue over normal brain tissue and achieves a higher brain-to-plasma ratio than TMZ, suggesting improved delivery to central nervous system malignancies.
NEO212 demonstrates robust cytotoxic activity against tumor cells that are resistant to TMZ, including those with high expression of the MGMT DNA repair enzyme-a major mechanism of resistance to standard TMZ therapy.
NEO212 exerts pleiotropic effects on cancer cells, including proliferation arrest, induction of differentiation, and cell death. Its cytotoxicity cannot be replicated by simply mixing TMZ and POH, indicating unique properties conferred by the conjugation.
Preclinical studies show NEO212 is better tolerated in animals than TMZ at equivalent or higher doses, with reduced bone marrow suppression and improved safety margins.
NEO212 causes DNA damage and cell death more efficiently than TMZ, likely due to increased biological half-life and greater opportunity for cytotoxic DNA lesion formation. It also induces reactive oxygen species (ROS) accumulation and downregulates MGMT protein levels.
Clinical Development
NEO212 is currently completing Phase I clinical trials for brain cancer, including glioblastoma, with the final patient cohort finishing dosing as of April 2025. The trial uses a dose-escalation design to establish safety and appropriate dosing.
In addition to gliomas and brain metastases, NEO212 is being explored for other cancers such as acute myeloid leukemia (AML), triple-negative breast cancer, and non-small cell lung cancer.
NEO212 is engineered to maintain effectiveness in both MGMT-positive and MGMT-negative gliomas, with the goal of reducing rapid bloodstream degradation and bone marrow toxicity that limit TMZ’s use.
Otto Warburg
Otto Heinrich Warburg, a German biochemist and physiologist born in 1883, made groundbreaking contributions to cellular metabolism and cancer research, earning him the Nobel Prize in Physiology or Medicine in 1931 for his work on respiratory enzymes.
Early Life and Education
Born on October 8, 1883, in Freiburg im Breisgau, Germany, Otto Heinrich Warburg grew up in a distinguished family environment. His father, Emil Warburg, was a renowned physicist and President of the Physikalische Reichsanstalt. Warburg pursued a comprehensive education, studying chemistry under Emil Fischer at the University of Berlin, where he obtained his doctorate in 1906. He then continued his studies at the University of Heidelberg, earning a medical doctorate in 1911 This dual expertise in chemistry and medicine laid the foundation for his future groundbreaking work in biochemistry and cell physiology.
Major Scientific Contributions
Groundbreaking research on cellular respiration and metabolism formed the cornerstone of Warburg's scientific legacy. His work on the process of oxidation in living cells led to the discovery of the iron-containing respiratory enzyme, cytochrome oxidase, for which he was awarded the Nobel Prize in 1931. Warburg's investigations extended to cancer metabolism, where he observed that tumor cells could thrive in anaerobic conditions, producing large quantities of lactic acid - a phenomenon later termed the Warburg effect.
Key contributions include:
Isolation of flavoproteins (yellow enzymes) involved in biological dehydrogenations by 1932
Discovery of nicotinamide as a component of hydrogen-transferring enzymes in 1935
Pioneering work on photosynthesis, including the discovery of the I-quantum reaction that splits CO2
Development of manometry techniques for studying oxygen consumption rates in living tissue
Demonstration that cancer cells can develop even in the absence of oxygen.
Career Milestones
Appointed professor at the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem in 1918, Warburg's career reached new heights when he became director of the Kaiser Wilhelm Institute for Cell Physiology in 1931. Throughout his distinguished career, he was nominated for the Nobel Prize an impressive 47 times. Warburg's dedication to research was unwavering, as he continued his scientific pursuits until the age of 86. His work attracted international recognition, leading to his election as a Foreign Member of the Royal Society in London in 1934 and memberships in various prestigious academies including Berlin, Halle, Copenhagen, Rome, and India.
Enduring Legacy in Science
Despite facing discrimination during the Nazi era due to his Jewish heritage, Warburg's scientific reputation allowed him to continue his work in Germany. His research has experienced a resurgence in recent years, particularly in the field of cancer metabolism. Contemporary scientists like Chi Van Dang have rediscovered the importance of Warburg's work, demonstrating that cancer cells are addicted to nutrients and lack the internal messaging to conserve resources when food isn't available. This renewed interest has led to new approaches in cancer research and treatment, solidifying Warburg's enduring impact on the scientific community decades after his death in 1970.
