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Cancer: An Odyssey Part 2: Siege Warfare

“Everyone has a doctor in him or her; we just have to help it in its work. The natural healing force within each one of us is the greatest force in getting well. Our food should be our medicine. Our medicine should be our food. But, to eat when you are sick, is to feed your sickness.”

— Hippocrates

Departing slightly away from our Trojan War framework established in Part 1, comes knowledge from an equally important historical Greek figure, Hippocrates, “The Father of Western Medicine.” You may notice I quote him a lot in my writing, as despite having an ignorance of the exact mechanisms, he had an insight into the nature of disease over 2,000 years ago, that are only fully beginning to appreciate today.

A hallmark of cancer, as discovered by Otto Warburg, is its abnormal and specialized utilization of glucose as a fuel, by way of aerobic glycolysis [1]. Thus, to eat carbohydrates, and to a lesser extent protein, in excess, is to feed the sickness. It was actually this very idea that let to the development of the ketogenic diet as a therapeutic strategy.

Since the time of Hippocrates, it was known that fasting was an effective method of controlling epilepsy, thus in the 1920's the ketogenic diet was born as a means of unlocking the metabolic benefits of fasting, i.e. reduced insulin signaling and increased production of ketone bodies, without the unfortunate side effect of perpetual fasting: DEATH [2].

To step back for a minute, there are a number of different theories regarding the mechanism which initiates those changes in cancer to favor aerobic glycolysis over oxidative phosphorylation; these include mitochondrial damage, genetic changes to oncogenes and tumor suppressor genes, increased hypoxia in aggressively metastatic tumors and chronically elevated insulin and inflammation [3].

The mitochondrial dysfunction theory [4] holds that insults to the mitochondria result in increased production of free radicals, or reactive oxygen species (ROS), with subsequent overexpression of hypoxia inducible factor (HIF)-1α, inactivation of the tumor suppressor genes and increased activity of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway [5]. Basically, mitochondrial damages causes the shift to aerobic glycolysis and allows the cells to grow uninterrupted in perpetuity.

The second theory is based on genetic mutations to the tumor suppressor genes and the hyperactivation of the insulin-like growth facor-1 receptor (IGFR1)-insulin receptor (IR)/PI3K/Akt/mTOR signaling pathway as the initiating factor [6]. As such, it is the mutations which lead to the subsequent mitochondrial damage and metabolic changes.

The hypoxia theory posits that the HIF-1α changes occur independent of mutations, but rather as a result of aggressive tumors moving too quickly for the vascularization and angiogenesis to keep up, leading to inadequate oxygen and a shift to glycolysis [3]. As a comparison, think of the shift to the lactic acid cycle (Cori cycle) following intense exercise when the body is unable to rapidly oxygenate the muscles [7].

The final theory is that elevated blood sugar, insulin and inflammatory cytokines signal the hyperactivation of the IGFR1-IR/PI3K/Akt/mTOR signaling pathway, independent of mutations, with a shift towards aerobic glycolysis and a decreased ability for apoptosis (programmed cell suicide) in damaged cells [8]. In this case, it is the inflammatory nature of the hyperglycemic foods abundant in the Western diet that leads to the development and progression of cancer. [9].

Now, with all of that being said, regardless of which mechanism proves correct, there is still a fundamental change in the way in which cancer metabolizes energy.

However, these changes are also something that can be manipulated!

Fasting and dietary restriction work by reducing insulin levels and turning down the IGFR1-IR/PI3K/Akt/mTOR signaling pathway [10]. Moreover, they act as hormetic stressors which create a differential stress resistance to oxidative stress, that protects the normal cells while further weakening the cancer cells [11].

Fortunately, the ketogenic diet, which as we discussed earlier was designed to mimic fasting, exhibits this same protective effect against oxidative stress [12], particularly, through the production of the ketone body, β-hydroxybutyrate [13].

Now, this is where things get really interesting. Part of the metastasis process is by way of increased production of free radicals, which damage the mitochondria of surrounding and further away cells, leading to the cancer spreading [14]. In fact, a reason why cancer cells sequester so much glucose may be as a means of compensating for the increased free radical generation [15].

As such, they are particularly sensitive to conditions of decreased sugar availability. Whereas normal cells can adapt to the utilization of ketones for energy, the cancer cells cannot efficiently metabolize them, thus making them uniquely vulnerable to one of their very own methods of transmission [16].

They ramp up free radical production in order to proliferate, but in the absence of glucose as a substrate, the inability to properly eliminate them fast enough can end up killing them! The greed of cancer cells in switching to aerobic glycolysis allows it to grow quickly and spread aggressively, but it lacks the metabolic flexibility to survive on other substrates.

“The god has granted you the actions of warfare... but you cannot choose to have all gifts given to you together.” .”

— Polydamas of Troy, The Iliad.

Harkening back to our Trojan War allegory, if we conduct siege warfare which starves the cancer cells, we will be able to induce internal struggle that causes our enemy to collapse under the it's own weight.

From there, these cells will be susceptible to attack from the various other therapies, both head on and through the back door, as a Trojan horse.

Perhaps the lack of efficacy of some alternative modalities in the scientific literature (besides due to lack of funding) is that they are missing this vital component. Caloric and specific macronutrient restriction, by way of the ketogenic diet, opens the door to a cascade of metabolic pathways that will synergistically improve the effectiveness of the other treatments!

Throughout the rest of our series, we will further explore the individual therapies and discuss their mechanisms of action, as well as relate to how they will be optimized when used in conjunction with the ketogenic diet. So be sure to stay tuned!

However, if you would like more information on how to properly implement a ketogenic diet for yourself, I highly recommend you pick up a copy of The Micronutrient Miracle, by my good friends Dr. Jayson and Mira Calton. It provides the foundational template for the dietary protocol I am currently using with my father.

“Here is the chance you've prayed for: now to hack them up... while they're in trouble... losing their footing. Fortune favors men who dare .”

— Turnus, King of the Rutuli, The Aenid.


1) Warburg, O. (1956). On the origin of cancer cells. Science. Vol. 123(3191):309–314.

2) Wheless, J.W. (2008). History of the ketogenic diet. Epilepsia. Vol. 49 (Suppl 8):3-5.

3) Klement, R.J. & Kämmerer, U. (2011). Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr Metab. Vol. 8:75.

4) Seyfried, T.N., Flores, R.E., Poff, A.M. & D’Agostino, D.P. (2014). Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. Vol. 35(3):515-527.

5) Pelicano, H., Xu, R., Du, M., Feng, L., Sasaki, R., Carew, J.S., Hu, Y., Ramdas, L., Hu, L., Keating, M.J., Zhang, W., Plunkett, W. & Huang, P. (2006). Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J Cell Bio. Vol 175(6):913–923.

6) Robey, R.B. & Hay, N. (2009). Is Akt the “Warburg kinase”?— Akt-energy metabolism interactions & oncogenesis. Semin Cancer Biol. 19(1):25.

7) Draoui, N. & Feron, O. (2011). Lactate shuttles at a glance: From physiological paradigms to anti-cancer treatments. Dis Mod Mech. Vol. 4(6):727-732.

8) Pollack, M. (2008). Insulin & insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. Vol. 8(12):915-928.

9) Melnik, B.C., John, S.M. & Schmitz, G. (2011). Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: Lessons learnt from Laron syndrome. Nutr Metab. Vol. 8:41.

10) Santos, J., Leitão-Correia, F., Sousa, M.J. & Leão, C. (2016). Dietary restriction & nutrient balance in aging.Oxid Med Cell Long. Vol. 2016:4010357:10 pp.

11) Lee, C. & Longo, V.D. (2011). Fasting vs dietary restriction in cellular protection & cancer treatment: From model organisms to patients. Oncogene. Vol. 30(30):3305-3316.

12) Veech, R.L. (2004). The therapeutic implications of ketone bodies: The effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance & mitochondrial metabolism.Prostaglandins Leukot Essent Fatty Acids. Vol. 70(3):309-319.

13) Shimaz, T., Hirschey, M.D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C,A., Lim, H., Saunders, L.R., Stevens, R.D., Newgard, C.B., Farese , R.V. Jr., de Cabo, R., Ulrich, S., Akassoglou, K. & Verdin, E. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. Vol. 339(6116):211-214.

14) Reuter, S., Gupta, S.C., Chaturvedi, M.M. & Aggarwal, B.B. (2010). Oxidative stress, inflammation, & cancer: How are they linked? Free Rad Biol Med. Vol. 49(11):1603-1616.

15) Aykin-Burns, N., Ahmad, I.M., Zhu, Y., Oberley, L.W. & Spitz, D.R. (2009). Increased levels of superoxide & hydrogen peroxide mediate the differential susceptibility of cancer cells vs. normal cells to glucose deprivation. Biochem J. Vol. 418(1):29–37. 16) Poff, A.M., Ari, C., Seyfried, T.N. & D’Agostino, D.P. (2013). The ketogenic diet & hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS ONE. Vol. 8(6):e65522:9 pp.

** This post may contain affiliate links. If you make a purchase through an affiliate link, Paleo/ Primal Long Island will receive a very small commission, but your cost will not change. Thank you for supporting my blog!

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