Based on Dominic D’Agostino’s lecture in Nutrition Network’s Cancer Training

Reviewed by Tamzyn Murphy, RD, MSc

In the realm of cancer research and therapy, innovative approaches are continually being explored to enhance treatment efficacy and improve patient outcomes. One such avenue of investigation involves the combined use of ketosis and hyperbaric oxygen therapy (HBOT) as complementary strategies in cancer management. These approaches, rooted in scientific research and clinical trials, hold promise in altering cancer metabolism, reducing tumor growth, and enhancing the body’s ability to combat cancer cells. In this comprehensive blog, we delve into the intricacies of ketosis, hyperbaric oxygen therapy, and their potential synergy in targeting cancer metabolism.

Understanding Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) involves administering 100% oxygen at elevated pressure levels, independent of hemoglobin. This method allows oxygen to diffuse through the plasma, reaching areas with erratic blood flow or vessels, including tumors. Research has shown that HBOT can reverse tumor hypoxia, inhibit oncogenic drivers, and increase reactive oxygen species within tumors, thereby stimulating the immune response against cancer cells.

Early experiments in cell cultures, including brain cancer cells and healthy neurons, revealed the selective vulnerability of cancer cells to high levels of oxygen induced by HBOT. This vulnerability stems from the Warburg effect, characterized by impaired mitochondrial respiration and compensatory fermentation in cancer cells. As a result, cancer cells exhibit elevated production of reactive oxygen species, making them susceptible to hyperoxia-induced cell death.

Unraveling the Warburg Effect and Cancer Metabolism

The Warburg effect, elucidated by Otto Warburg, describes the metabolic shift in cancer cells towards glycolysis, even in the presence of oxygen. This phenomenon promotes tumor growth, chemo- and radiation resistance, and the progression of aggressive cancer phenotypes. Factors contributing to the Warburg effect include tumor hypoxia, elevated glucose and lactate levels, insulin signaling pathways, reactive oxygen species, inflammation, and immune suppression.

Ketogenic and low-carb diet therapies offer a promising approach to counteracting the Warburg effect. By reducing glucose availability and insulin signaling, ketogenic diets shift cellular metabolism towards utilizing ketone bodies as a primary energy source. These diets have been shown to inhibit tumor growth, enhance anti-tumor immunity, and improve overall treatment outcomes in various cancer models.

Preclinical Research: Exploiting HBOT and Ketosis

Preclinical studies have demonstrated the potential synergy between HBOT and ketosis in targeting cancer metabolism. Combining therapeutic ketosis with HBOT in animal models resulted in a significant increase in survival compared to either therapy alone. Ketone supplementation, both as a standalone intervention and in combination with a ketogenic diet, showed promising results in suppressing tumor growth and extending survival in preclinical models of cancer.

Clinical Trials and Human Studies

The clinical translation of HBOT and ketogenic diets in cancer therapy is supported by a growing body of evidence from human studies and clinical trials. Research indicates that HBOT, particularly in conjunction with radiotherapy, can enhance treatment efficacy by increasing tumor oxygenation levels. Ketogenic diets have been investigated in various cancer types, including glioblastoma, pediatric brain cancer, breast cancer, prostate cancer, and head and neck cancer.

Clinical trials exploring the use of ketogenic diets as adjuvant therapies alongside standard cancer treatments have shown promising results in improving biomarkers associated with better outcomes, reducing tumor progression, and enhancing quality of life in cancer patients. Additionally, ketosis has been implicated in reducing muscle catabolism and mitigating cancer cachexia, further highlighting its multifaceted benefits in cancer management.

Future Directions and Conclusion

The integration of ketosis and HBOT represents a novel and promising approach in the multifaceted landscape of cancer therapy. Continued research efforts are needed to elucidate the underlying mechanisms of action, optimize treatment protocols, and explore potential synergies with existing cancer therapies. By targeting cancer metabolism through metabolic interventions like ketosis and enhancing tumor oxygenation with HBOT, we hold the key to unlocking new avenues for improving cancer treatment outcomes and enhancing patient well-being.

In conclusion, the convergence of ketosis and hyperbaric oxygen therapy presents a compelling strategy for disrupting cancer metabolism and enhancing the body’s natural defenses against cancer cells. As research in this field advances, the potential for innovative and integrative approaches to cancer therapy continues to expand, offering hope for improved outcomes and better quality of life for cancer patients worldwide.

We are pleased to announce our latest training, Cancer: A Metabolic Disease. The training curriculum is presented by national and international medical and allied healthcare experts in the field of cancer research. Through delving into the mechanisms underlying cancer, the implementation of TCR and fasting in cancer treatment, practitioners will be equipped with the tools needed for holistic cancer patient management. Through lecturer guidance and expertise, learners will gain a deep understanding of the intricacies involved in implementing and optimizing this approach, paving the way for improved health outcomes and a transformative understanding of the role carbohydrates play in our overall well-being.

Now open for enrollment at a discounted, early bird rate of 20% off. This discount is valid until the launch date on 29 February 2024.

References

1. Aronica L, Volek J, Poff A.D’Agostino DP. Genetic variants for personalised management of very low carbohydrate ketogenic diets. BMJ Nutrition, Prevention & Health 2020Dec12;3(2):363-373. PMID: 33521546; doi: 10.1136/bmjnph-2020-000167 ).
2. Norwitz NG, Winwood R, Stubbs BJ,D’Agostino DPand Barnes PJ. “Case report: Anti-inflammatory ketogenic diet improves Chronic Obstructive Pulmonary Disease”Frontiers inMedicine, section Pulmonary Medicine, July 2021https://doi.org/10.3389/fmed.2021.6994273.
3. Stavitzski NM, Landon CS, Hinojo CM, Poff AM, Rogers CQ,D’Agostino DP, Dean JB. Exogenous Ketone Ester Delays CNS Oxygen Toxicity Without Impairing Cognitive and MotorPerformance in Male Sprague Dawley Rats. Am J Physiol Regul Integr Comp Physiol. 2021 Jun 16. doi: 10.1152/ajpregu.00088.2021. PMID: 34132115.4.
4. Gambardella I, Ascione G,D’Agostino DP, Ari C, Ivascu N, Villena-Vargas J, Girardi L. Neuroprotection of Ketosis in Acute Injury of the Mammalian Central Nervous System: a Meta-Analysis.J Neurochem. 2021; 00: 1–14.PMID: 33675563.https://doi.org/10.1111/jnc.153415.
5. Hinojo CM, Ciarlone GE,D’Agostino DP, Dean JB. Exogenous ketone salts inhibit superoxide production in the rat caudal solitary complex during exposure to normobaricandhyperbaric hyperoxia.J Appl Physiol.2021 Mar 4. PMID: 33661724. doi: 10.1152/japplphysiol.01071.2020 .
6. Kovacs Z,D’Agostino DP, Dobolyi A, Ari C. Adenosine A1 receptor antagonism abolished the anti-seizure effects of exogenous ketone supplementation in Wistar Albino Glaxo Rijswijkrats. June 2017 Front. Mol. Neurosci. doi: 10.3389/fnmol.2017.002357.
7. Egan B,D’Agostino DP. (2016) Fueling Performance: Ketones Enter the Mix. Cell Metabolism. Sep 13;24(3):373-5. doi: 10.1016/j.cmet.2016.08.0218.
8. Ciarlone SL; Grieco JC,D’Agostino DP, Weeber E. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticityin anAngelman syndrome mouse model. Neurobiology of Disease (2016) Dec;96:38-46. doi: 10.1016/j.nbd.2016.08.002.9.
9. Viggiano A, Pilla R, Arnold P, Marcellino M,D’Agostino DP, Coppola G. (2015) Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure. Brain Res.2015 May 27. pii: S0006-8993(15)00425-4. DOI: 10.1016/j.brainres.2015.05.023.10.
10. Youm Y, Nguyen K, Grant RW, Golgberg EL, Bodogai M, Kim D,D’Agostino DP, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A,Alnemri E, Dixit VD. “Ketone bodyβ-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nature Medicine, 2015 Mar;21(3):263-9 DOI: 10.1038/nm.3804.11.
11. D’Agostino, D.P., Pilla, R., Held, H.E., Landon, C.S., Puchowicz, M., Brunengraber, H., Ari, C., Arnold, P. and Dean, J.B. Therapeutic ketosiswith ketone ester delays central nervoussystem oxygen toxicity seizures in rats. AJP Regulatory, Integrative and Comparative Physiology, 2013 May 15;304(10):R829-36. DOI: 10.1152/ajpregu.00506.2012.12.
12. Viggiano A, Pilla R, Arnold P, Marcellino M,D’Agostino DP, Zeppa P, Coppola G. Different calorie restriction treatments have similar anti-seizure efficacy.Seizure-European Journal ofEpilepsy; 2016 Feb;35:45-9. doi: 10.1016/j.seizure.2016.01.00313.
13. Koutnik AP, Poff AM, Ward NP, DeBlasi JM, Soliven MA, Romero MA, Roberson PA, Fox CD, Roberts MD,D’Agostino DP. Ketone Bodies Attenuate Wasting in Models of Atrophy.2020 Apr 2. J Cachexia Sarcopenia Muscle. 2020;10.1002/jcsm.12554. doi:10.1002/jcsm.1255414.
14. Koutnik AP,D’Agostino DP,Egan B. The Anti-Catabolic Effects of Ketone Bodies. Trends in Endocrinology and Metabolism. 2019 Apr;30(4):227-229. doi: 10.1016/j.tem.2019.01.006.15.
15. Hernandez A, Truckenbrod L, Federico Q, Campos K, Moon B, Ferekides N, Hoppe M, D’Agostino D, Burke S. Metabolic switching isimpaired by aging and facilitated by ketosisindependent of glycogen. Aging (Albany NY). 2020 May 5;12(9):7963-7984. doi: 10.18632/aging.103116. Epub 2020 May 5. PMID: 32369441