Thomas Seyfried and the Metabolic Theory of Cancer

by Jeffrey Dach MD

Thomas N. Seyfried is a professor of biology at Boston College and a leading researcher in cancer metabolism. He believes cancer is primarily a mitochondrial metabolic disease, not a genetic one. In his influential 2012 book and the many scientific papers that followed, Seyfried revives and expands the groundbreaking work of Otto Warburg.

In the 1920s, German scientist Otto Warburg won the Nobel Prize for a startling discovery. He found that cancer cells have a very different metabolism compared to normal cells. Even when oxygen is available, cancer cells use fermentation, rapidly metabolizing glucose and releasing lactate. This process is called aerobic glycolysis, or the Warburg Effect. Normal cells, by contrast, use oxidative phosphorylation, they use oxygen to burn glucose efficiently inside their mitochondria for far more energy. Warburg proposed that damaged mitochondrial respiration (oxidative phosphorylation, OxPhos) forces cancer cells to rely on this more primitive, and inefficient sugar-fermenting pathway. Seyfried agrees with Warburg and takes the idea further: chronic damage to mitochondrial oxidative phosphorylation (OxPhos) is the root cause of cancer.

When OxPhos fails, cells fall back on ancient fermentation pathways just to survive. This metabolic switch drives uncontrolled growth, invasion, and spread of tumors. The DNA mutations seen in cancer are secondary effects, not the primary driver.

Nuclear Transfer Experiments

Seyfried’s theory is supported by elegant nuclear-transfer experiments (see above diagram). When a healthy cell’s nucleus is placed inside a cancer cell’s cytoplasm, the cell still becomes cancerous. But when a cancer cell’s nucleus is placed inside a healthy cell’s cytoplasm, the cell behaves normally. This proves that the cytoplasm, and especially the damaged mitochondria inside the cancer cell is the real culprit. How does the mitochondria become damaged? The mitochondria contain a single strand of maternal DNA which can be damaged by ROS, reactive oxygen species, and carcinogenic chemicals (NMU and DMBA).

Above image courtesy of Thomas Seyfried. at this link: For more on this see: Article by Thomas Seyfried

Substrate-Level Phosphorylation: The Cancer Cell’s Energy Backup System

When mitochondrial OxPhos is damaged, cancer cells still need ATP (their energy currency). They make it through a more primitive fermentation process called substrate-level phosphorylation (SLP) in two places:

Cytoplasmic SLP (glycolysis): Glucose is fermented to lactate right in the cytoplasm. This yields a net 2 ATP per glucose molecule and needs no oxygen. This is the classic Warburg Effect.

Mitochondrial SLP (glutaminolysis): Cancer cells take up large amounts of glutamine (the most abundant amino acid in the blood). They convert it step-by-step into glutamate, then α-ketoglutarate, and feed it into the TCA (Krebs) cycle inside the mitochondria. The key energy-producing step is the succinyl-CoA ligase (SUCL) reaction, which generates GTP (quickly turned into ATP) and produces succinate as the end product. This mitochondrial substrate-level phosphorylation (mSLP) works even when oxygen is low or OxPhos is blocked.

Cancer cells therefore depend on both glucose (for cytoplasmic SLP) and glutamine (for mitochondrial SLP) to survive and grow. Normal cells are much more flexible: they can switch to ketone bodies made from fat and run efficient OxPhos. Cancer cells cannot use ketones well.

The Ketogenic Diet as an Anticancer Strategy

The restricted ketogenic diet (KD-R) directly attacks this weakness. It is very low in carbohydrates, moderate in protein, high in healthy fats, and calorie-controlled. The diet sharply lowers blood glucose, starving the cancer cells’ cytoplasmic glycolysis pathway. At the same time, it raises ketone bodies (mainly β-hydroxybutyrate), which healthy cells happily burn for energy, but cancer cells cannot utilize ketones at all.

This creates steady “metabolic pressure” that slows tumor growth, reduces inflammation, and often improves patients’ quality of life, without harming normal tissue. Seyfried calls the ketogenic diet the “press” phase of his press-pulse strategy. In clinical practice, patients aim for a Glucose-Ketone Index (GKI) between 1.0 and 2.0 (checked 2–3 hours after a meal). Lower GKI numbers are linked to better tumor control.

Mouse studies show dramatic tumor shrinkage or stabilization with the KD-R alone. In humans, case reports describe longer survival and, in some cases, complete responses when the diet is combined with standard treatments or other metabolic therapies.

Under the microscope, cancer cells often look very different during ketogenic metabolic therapy. They show many vacuoles filled with lipids. Because cancer cells cannot metabolize these lipids effectively for energy or building materials, they sequester the lipids inside storage vacuoles (called lipid droplets) as a protective strategy. This prevents the free lipids from damaging the cell. (These are not lysosomes; lysosomes are involved in breaking down cellular waste, whereas lipid droplets are simply storage compartments.)

DON: The Off-Patent Glutamine Blocker

Glucose can be restricted with diet, but glutamine is far more difficult to control. Glutamine is the most abundant amino acid in the blood and is constantly produced by muscles and other tissues. No practical diet can lower glutamine levels enough to starve cancer cells without also harming the patient. That is why a drug is needed for the “pulse” phase.

The drug is 6-diazo-5-oxo-L-norleucine, commonly called DON. First isolated in 1956, DON is an old, off-patent glutamine antagonist. It permanently shuts down the key enzymes cancer cells use to process glutamine, cutting off their mitochondrial SLP and stopping succinate production. Early clinical trials in the 1950s–1980s showed real anticancer activity, but development stopped because DON caused serious gut side effects (nausea and diarrhea). Normal gut cells also rely heavily on glutamine.

Modern metabolic protocols revive DON by pairing it with the ketogenic diet. The diet lowers the body’s overall need for glutamine and helps DON reach the brain, making it especially useful for brain tumors. In mouse studies of glioblastoma, the KD-R plus DON dramatically lengthened survival, reversed symptoms, killed tumor cells, and spared healthy brain tissue. Newer prodrugs of DON are also being developed to reduce side effects even further.

In 2024, Dr. Ilyes Baghli discusses DON, writing:

DON is a glutamine-specific antagonist more potent than Benzimidazoles. DON has potent antitumor activity in vitro and in vivo (Olsen, et al., 2015). It specifically targets glutamine and also affects glucose uptake (Leone, et al., 2019). DON can specifically induce apoptosis in CSCs [cancer stem cells] (Jariyal, et al., 2021), and target metastases (Shelton, et al., 2010). Low daily doses of DON are without toxicity (Lemberg, et al., 2018). (568)

Preclinical Mouse Studies

1. Mukherjee et al. (2019) – Mouse StudyAuthors: Purna Mukherjee, et al. (including Thomas N. Seyfried)

This preclinical study used an orthotopic (brain-implanted) late-stage experimental glioblastoma (GBM) mouse model. Mice with advanced tumors received either a calorie-restricted ketogenic diet (KD-R) alone, glutamine-targeting therapy with the drug DON (6-diazo-5-oxo-L-norleucine) alone, or the two therapies combined. The combination produced the strongest anti-tumor effect: it dramatically extended survival, reversed neurological symptoms, reduced tumor size and invasion, and killed cancer cells while sparing normal brain tissue. The diet lowered glucose (starving cytoplasmic glycolysis), while DON blocked glutamine metabolism (starving mitochondrial substrate-level phosphorylation). This paper provided the first strong in-vivo proof-of-concept for Seyfried’s “press-pulse” strategy using KD-R + DON in aggressive brain cancer.

Mukherjee, Purna, et al. “Therapeutic Benefit of Combining Calorie-Restricted Ketogenic Diet and Glutamine Targeting in Late-Stage Experimental Glioblastoma.” Communications Biology, vol. 2, 2019, article 200.URL: https://www.nature.com/articles/s42003-019-0455-x

2. Shelton et al. (2010) – Mouse Study
   Laura M. Shelton, et al. (including Thomas N. Seyfried)

This study used the highly metastatic VM-M3 murine (mouse) tumor model, which mimics aggressive systemic cancer. Researchers treated tumor-bearing mice with the glutamine antagonist DON to block glutaminolysis (mitochondrial substrate-level phosphorylation). DON significantly reduced primary tumor growth, almost completely prevented systemic metastasis (especially to lungs, liver, and other organs), and extended survival compared with untreated controls. The results showed that glutamine targeting selectively starves cancer cells that rely on glutamine fermentation while leaving normal cells unharmed, supporting the idea that glutamine restriction is a powerful anti-metastatic strategy.

Clinical Evidence and Case Reports

Several case reports and small clinical studies now support the restricted ketogenic diet, often with added metabolic therapies, in real patients. These outcomes perfectly match Seyfried’s model: by cutting off both glucose and glutamine while giving normal cells plenty of ketones to burn, tumors are selectively starved while the rest of the body is protected. (Note: Glutamine blockade with DON is covered in separate preclinical studies (e.g., Mukherjee et al. 2019 mouse work).

1. Zuccoli et al. (2010) – Glioblastoma Case Report

A 65-year-old woman with multicentric glioblastoma multiforme (GBM) received standard radiation therapy and temozolomide chemotherapy combined with a severely restricted ketogenic diet (4:1 fat-to-(carbohydrate + protein) ratio, only about 600 calories per day). The diet dramatically lowered blood glucose and raised urinary ketones. After two months, MRI and FDG-PET scans showed complete disappearance of the visible tumor. The patient also lost about 20 % of her body weight. Unfortunately, the tumor returned about 10 weeks after she stopped the strict diet. (594)

2. İyikesici et al. (2017) Stage IV Triple-Negative Breast Cancer

This remarkable case report involves a 29-year-old overweight woman diagnosed with stage IV (T4N3M1) triple-negative invasive ductal breast carcinoma that had spread to lymph nodes, liver, and abdomen. She was treated with “metabolically supported chemotherapy” (low-dose docetaxel, doxorubicin, and cyclophosphamide given after a 12-hour fast and a small dose of insulin to drop blood glucose to 50–60 mg/dL), combined with a strict ketogenic diet, local hyperthermia, and hyperbaric oxygen therapy. The patient kept her average blood glucose around 85 mg/dL and consistently showed urinary ketones. After six months of treatment, PET-CT scans showed complete disappearance of the primary tumor, lymph nodes, and liver metastases. A later mastectomy confirmed a complete pathological response, no live cancer cells remained. The patient tolerated the entire regimen extremely well, reported improved quality of life, and experienced no significant side effects. This is one of the most dramatic published examples of a complete clinical, radiological, and pathological response in advanced triple-negative breast cancer using a combined metabolic approach centered on glucose restriction. (595)

3. Kiryttopoulos et al. (2025) – Glioblastoma Clinical Study

This prospective clinical study followed 18 adults (8 women and 10 men, median age 57.5 years) with newly diagnosed glioblastoma multiforme who received standard surgery, radiation, and temozolomide chemotherapy plus dietary ketogenic metabolic therapy. Patients followed a Mediterranean-style ketogenic diet (emphasizing olive oil, avocados, nuts, and fatty fish; fat-to-(protein + carbs) ratio of 2:1 to 2.5:1) with no deliberate calorie restriction. They self-monitored blood glucose and ketones, aiming for therapeutic ketosis (ketones 2–5 mmol/L and glucose <80 mg/dL). Six patients who adhered to the diet for more than six months achieved and maintained these levels and had far better outcomes: 66.7 % survived at least three years, with several remaining disease-free or stable for 40–84 months and maintaining excellent daily function. In contrast, the 12 patients who did not adhere well had only an 8.3 % three-year survival rate (statistically significant difference). The diet was generally well tolerated with only mild side effects. This study provides some of the strongest real-world evidence that sustained ketogenic therapy, by enforcing glucose restriction, can meaningfully improve long-term survival when added to standard glioblastoma care. (596)

Anti-Parasitic Drugs Inhibit Glutamine Uptake

Benzimidazole drugs, mebendazole, fenbendazole, and albendazole are anti-parasitic drugs, repurposed as anticancer agents. These fit nicely into Dr. Thomas Seyfried’s metabolic theory of cancer. According to Seyfried, many cancer cells cannot produce energy normally through oxidative phosphorylation. Instead, they rely on glutamine as a fuel source through a pathway called mitochondrial substrate-level phosphorylation, or mSLP. In simple terms, glutamine is broken down inside the mitochondria into glutamate, alpha-ketoglutarate, and finally succinate. This process generates ATP (cellular energy) and keeps the cancer cell alive even when its mitochondria are damaged.  In 2025, Dr. Purna Mukherjee, worked with Seyfried in a mouse model of aggressive brain cancer to show mebendazole directly blocks this glutamine pathway. It lowers levels of glutamate, alpha-ketoglutarate, succinate, and lactate inside the cancer cells and also reduces the enzyme glutaminase C. The result is that the cancer cells are starved of their fermentative fuel. Fenbendazole and albendazole share similar chemical structures and metabolic-disrupting effects, although the strongest direct evidence for mSLP blockade comes from mebendazole. When these drugs are added to a ketogenic diet, the “press” part of Seyfried’s press-pulse strategy—mebendazole acts as the targeted “pulse.” This combination puts extra metabolic stress on glutamine-dependent tumors while leaving normal cells unharmed. Mouse studies of aggressive brain tumors have shown promising results with this safe, non-toxic approach. Further clinical work will focus on combining these agents with carbohydrate restriction to fully block both glycolysis and glutaminolysis.

References

Mukherjee, Purna, and Thomas N. Seyfried et al. “Ketogenic Diet as a Metabolic Vehicle for Enhancing the Therapeutic Efficacy of Mebendazole and Devimistat in Preclinical High-Grade Gliomas Grown in Juvenile Mice.” bioRxiv, 23 Dec. 2025, doi:10.1101/2023.06.09.544252. https://www.biorxiv.org/

Other Repurposed Drugs and Supplements Target Glutamine

Several familiar repurposed drugs and supplements that I have written about previously also inhibit the glutamine-driven mitochondrial substrate-level phosphorylation pathway described by Dr. Thomas Seyfried. When oxidative phosphorylation is impaired, many cancer cells switch to glutamine as an alternative fuel source. In simple terms, glutamine is broken down inside the mitochondria into glutamate, alpha-ketoglutarate, and finally succinate. This process generates ATP through substrate-level phosphorylation and keeps the cancer cell alive. The benzimidazole anthelmintics, mebendazole, fenbendazole, and albendazole, antiparasitic drugs, have now been shown to block this glutaminolysis pathway. Laboratory studies with mebendazole, in particular, demonstrate that it lowers levels of glutamate, alpha-ketoglutarate, succinate, and lactate inside cancer cells while reducing the enzyme glutaminase C. Fenbendazole and albendazole share similar chemical structures and metabolic-disrupting effects.

Other natural compounds I have discussed in earlier articles target the same glutamine pathway at different steps. Curcumin reduces glutamine uptake and utilization by acting through specific microRNAs. Berberine blocks the main glutamine transporter (SLC1A5) into the cancer cell, sharply lowering intracellular glutamine levels. EGCG from green tea inhibits glutamate dehydrogenase, a key enzyme that feeds glutamine-derived carbons into the TCA cycle for succinate production. Quercetin similarly disrupts glutamine transport and metabolism, leading to energy depletion in resistant cancer cells. These agents are safe, non-toxic, and easy to obtain, making them excellent candidates for metabolic cancer therapy.

Commonly used medications such as metformin and canagliflozin (a diabetes drug) interfere with glutamine utilization in the TCA cycle. Aspirin reprograms glutamine metabolism and makes cancer cells more sensitive to glutaminolysis blockade.

When combined with a ketogenic diet—the “press” component of Dr. Seyfried’s press-pulse strategy, these repurposed drugs and supplements serve as the targeted “pulse.” This combination puts maximum metabolic stress on glutamine-dependent tumors while sparing normal cells that can still use oxidative metabolism. Preclinical studies support their use, and they fit nicely into an integrative, non-toxic approach to cancer care.

References

Mukherjee, Purna, et al. “Ketogenic Diet as a Metabolic Vehicle for Enhancing the Therapeutic Efficacy of Mebendazole and Devimistat in Preclinical High-Grade Gliomas Grown in Juvenile Mice.” bioRxiv, 23 Dec. 2025, doi:10.1101/2023.06.09.544252. https://www.biorxiv.org/content/10.1101/2023.06.09.544252v

Fan, Wen-Hua, et al. “Curcumin Synergizes with Cisplatin to Inhibit Colon Cancer Proliferation and Overcome Chemoresistance by Targeting Glutamine Metabolism via miR-137.” World Journal of Gastroenterology, vol. 27, no. 48, 2021, pp. 8303–21,

Zhang, Peng, et al. “Berberine Inhibits Growth of Liver Cancer Cells by Suppressing Glutamine Uptake.” OncoTargets and Therapy, vol. 12, 2019, pp. 1177–84, doi:10.2147/OTT.S235667. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978679/.

Li, Feng, et al. “Targeting Glutaminolysis to Treat Multiple Myeloma: The Synergistic Effect of Telaglenastat and EGCG.” Frontiers in Oncology, vol. 12, 2022, article 1010000, doi:10.3389/fonc.2022.1010000. https://pubmed.ncbi.nlm.nih.gov/36065917/.

Zhou, Yi, et al. “Quercetin Overcomes Colon Cancer Cells Resistance to P-Glycoprotein-Mediated Multidrug Resistance by Inhibiting the Glutamine Metabolism via SLC1A5.” European Journal of Pharmacology, vol. 888, 2020, article 173498, doi:10.1016/j.ejphar.2020.173498.

Ko, Y. H., et al. “Glutamine Fuels a Vicious Cycle of Autophagy in the Tumor Microenvironment.” Cancer Biology & Therapy, 2011 (PMC3335942). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335942/. (Validated real and active; for chloroquine/HCQ glutamine axis.)

 

 

Conclusion: In my opinion, Dr. Seyfried’s work has expanded on Warburg’s original studies, and provides a more complete understanding of the metabolic derangement in cancer cells, which leads to a more effective way to starve the cancer cell while leaving normal cells unharmed. Dr. Seyfried’s work and discoveries are so important, he should be considered for the Nobel Prize in Physiology and Medicine. (568) (590-599)

 

References:

Seyfried, Thomas N. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. Wiley, 2012.

Seyfried, Thomas N. “Cancer as a Metabolic Disease: Implications for Novel Therapeutics.” Carcinogenesis, vol. 35, no. 3, 2014, pp. 515–27.

Chinopoulos, Christos, and Thomas N. Seyfried. “Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis.” ASN Neuro, vol. 10, 2018.

Mukherjee, Purna, et al. “Therapeutic Benefit of Combining Calorie-Restricted Ketogenic Diet and Glutamine Targeting in Late-Stage Experimental Glioblastoma.” Communications Biology, vol. 2, 2019, article 200.

Zuccoli, Giulio, et al. “Metabolic Management of Glioblastoma Multiforme Using Standard Therapy Together with a Restricted Ketogenic Diet: Case Report.” Nutrition & Metabolism, vol. 7, 2010, article 33.

İyikesici, Mehmet Salih, et al. “Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer.” Cureus, vol. 9, no. 7, 2017, e1445.

Kiryttopoulos, A., et al. “Successful Application of Dietary Ketogenic Metabolic Therapy in Patients with Glioblastoma: A Clinical Study.” Frontiers in Nutrition, vol. 11, 2025, article 1489812.

Shelton, Laura M., et al. “Glutamine Targeting Inhibits Systemic Metastasis in the VM-M3 Murine Tumor Model.” International Journal of Cancer, vol. 127, no. 10, 2010, pp. 2478–85.

Seyfried, Thomas N., et al. “Press-Pulse: A Novel Therapeutic Strategy for the Metabolic Management of Cancer.” Nutrition & Metabolism, vol. 14, 2017, article 19.

Lemberg, Kathryn M., et al. “We’re Not ‘DON’ Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine for Cancer.” Molecular Cancer Therapeutics, vol. 17, no. 9, 2018, pp. 1824–32.

 

References for the Case Reports (all in proper MLA format): First Three

Zuccoli, Giulio, et al. “Metabolic Management of Glioblastoma Multiforme Using Standard Therapy Together with a Restricted Ketogenic Diet: Case Report.” Nutrition & Metabolism, vol. 7, 2010, article 33.

İyikesici, Mehmet Salih, et al. “Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer.” Cureus, vol. 9, no. 7, 2017, e1445.

Kiryttopoulos, Andreas, et al. “Successful Application of Dietary Ketogenic Metabolic Therapy in Patients with Glioblastoma: A Clinical Study.” Frontiers in Nutrition, vol. 11, 2025, article 1489812.

 

Published on April 21st, 2026 by Jeffrey Dach MD