Ketone supplementation and the ketogenic diet for cancer

Ketone enhancement by diet and supplementation can dramatically improve cancer survival. An easily implemented low carb high fat approach can produce results comparable to a more strict diet and be further enhanced by ketone supplementation.Glucose consumption at a ravenous rate is characteristic of the peculiar metabolism of cancer cells. Fresh evidence for the 'Warburg Effect' the metabolic theory of cancer is eclipsing the earlier ascendant somatic mutation theory. Accordingly, ketogenic LCHF (low carb high fat) diets are gathering momentum in the treatment and prevention of malignancies. A study recently published in Clinical Cancer Research offers evidence that an easily implemented LCHF ketogenic diet supplemented with MCTs (medium chain triglycerides; sHFLC) may render significant benefit in the treatment of glioblastoma, a very malignant and metabolically active brain cancer, while being easier to maintain than a more strict ketogenic diet. The authors state:

"Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations...We report a dietary intervention that produces low circulating glucose while elevating ketones and results in a substantial reduction in GB cellular proliferation."

Glucose metabolism and the Warburg Effect

The bizarre metabolism of cancer cells has been recognized has an especially promising vulnerable target for treatment.

"Glucose metabolism and the Warburg Effect have gained traction as a potential tumor weakness and exploitable treatment area. Where normal cells utilize glucose for high-yield energy production in the mitochondria (1:36ATP), tumor cells demand higher levels of glucose for diminished energy production, via lactate in the cytosol (1:4ATP) and nucleotide synthesis in the pentose phosphate pathway. This metabolic characteristic, termed the Warburg Effect, is an essential byproduct of rapid cellular proliferation and promoted during tumorigenesis by oncogenic metabolic reprogramming. Hence tumor cells acquire the ability to sustain proliferative signaling mechanisms, which subsequently promotes malignant glycolysis. "

Ketogenic diet

The ketogenic diet has been around has been demonstrated to be safe and effective but in its strict form can be difficult to maintain.

"Research into dysregulated cellular metabolism has given rise to the notion that dietary therapies for cancer patients may have significant clinical utility. GB has been proposed to be a promising candidate for dietary intervention due to its substantial reliance and utilization of glucose. At the forefront of dietary anticancer therapy is the ketogenic diet (KD), which is a high-fat, low-carbohydrate, low-protein diet, used for decades to treat refractory epileptic seizures. Extreme carbohydrate restriction mimics a fasting state, resulting in reduction of blood glucose and induction of ketone bodies (e.g., b-hydroxybutyrate/BHB). Ketone bodies are suitable energy replacements for normal cells with functional mitochondria, but have been shown to be unsuitable for tumor cells, as tumor cell mitochondrial functions are dysregulated. Existing preclinical data support the KD and a calorie-restricted KD (RKD) in the treatment of brain cancer by diminishing tumor growth and increasing animal survival. Clinical report, case reports, and pilot trials have demonstrated that the KD is safe, has low toxicity, and is applicable to cancer patients."

But because of challenges to implementation of the strict ketogenic diet the authors sought to investigate the effect of a more easily maintained less restrictive LCHF diet with supplemented with medium chain triglycerides (MCT).

"...a less restrictive KD-like diet that would exhibit the same physiologic phenotype and antitumor efficacy. By supplementing a high-fat, low-carbohydrate (sHFLC), moderate protein diet with specialized medium-chain triglycerides [MCT; 60%(30%):30%:10%::Fat(MCT): Protein:Carb], we hypothesize that a more balanced diet can be implemented, resulting in diminished tumor progression. MCTs were specifically chosen based on carbon chain lengths (C8: C10::97%:3%), which allow them to rapidly diffuse from the gastrointestinal tract into the hepatic portal system and travel directly to the liver where they are converted into ketone bodies). We believe it is possible to provide a more nutritionally complete, flexible, and palatable anticancer diet with the sHFLC, which could target a diverse patient population and increase patient compliance."

Tumor cell growth significantly reduced

They tested glioblastoma cells both in vivo and in vitro resulting in a significant decrease in the proliferation of both the tumor cells, and very importantly the tumor stem cells.

"Lowering glucose concentrations resulted in a significant reduction in Ki-67 and MCM2 expression, in both PG and LG as well as a significant increase in active caspase-3 between NG and LG. Therefore, alterations in glucose availability, to levels equivalent to a low glucose state, are sufficient to slow the proliferation of gliomaspheres while concomitantly increasing apoptosis...Quantification of the self-renewing stem cell symmetrical division rate demonstrated a significant decrease in cancer stem cell expansion under reduced glucose conditions. The combination of diminished stem cell division rates, cellular fold expansion, and proliferation markers indicates that lowering glucose affects not only the putative stem cell population, but also the non-stem cell population."

Low carb high fat benefits comparable to strict ketone diet

This is a very important point for practical implementation of an effective therapeutic diet.

"Animals placed on the sHFLC and KD had a significant reduction in blood glucose, above hypoglycemic levels, compared to controls, with no difference between the sHFLC and KD. Blood ketones were significantly increased in mice maintained on the sHFLC and KD to a safe level, with a statistical difference between the groups."

The employed a glucose ketone index (GKI) to compare dietary interventions:

"To compare blood glucose and ketone levels among different anticancer dietary therapies, a simple glucose ketone index (GKI) is used. The GKI is a single number, and can be used both clinically and preclinically, to identify a therapeutic zone. On the basis of this formulation, our average calculated GKIs are 24.4 ± 7.14, 3.1 ± 1.07, and 1.94 ± 0.67 for the control, sHFLC and KD, respectively."

Adding metformin yielded no additional benefit

Those following the topic of metformin as an anticancer therapy should note that it appears to be rendered unnecessary by this dietary approach:

"It has been proposed that a potential combinatorial treatment of metformin with carbohydrate restriction could result in enhanced antitumor efficacy. Mice fed the KD and sHFLC alone demonstrated a significant increase in survival compared with the control-fed mice, statistically equal to metformin alone. In both xenograft models, metformin alone was able to reduce blood glucose, reduce tumor progression, and increase survival, yet the combination sHFLC diet and metformin showed no additive or synergistic effects...These data indicate that the sHFLC diet is capable of increasing animal survival while minimizing tumor burden, is as effective as metformin, and may mechanistically overlap in AMPK-mediated inactivation of the mTOR pathway."

Most importantly...

"The sHFLC diet slows tumor progression, increases survival, and reduces tumor burden in subcutaneous and orthotopic xenograft models."

Low carb high fat with MCT oil much easier to maintain than strict ketogenic

Low carb high fat supplemented with MCT oil is as effective as the stricter ketogenic diet and has nutritional advantages.

"Here, we demonstrate that a high-fat, low-carbohydrate diet supplemented with MCT oil (sHFLC) is able to slow tumor progression and increase survival. In vivo, the sHFLC diet was similar to the ketogenic diet (KD) in antitumor efficacy, but showed nutritional advantages in body weight, organ enzyme levels, and lipid profile. Finally, we demonstrate that the sHFLC diet affects the mTOR signaling pathway by reducing expression of upstream regulators and translational downstream effectors...We designed the sHFLC diet for long-term sustainable maintenance of GB and for increased flexibility and palatability."

Clinical note: Clearly, glucose control is crucial in case management for treatment and prevention of malignancies.

"Excess glucose, as seen in GB patients with persistent hyperglycemia, leads to poor patient survival. It has also been suggested that diets with a high glycemic index may increase the risk of tumorigenesis, and low-carbohydrate, high-protein diets that limit circulating glucose can delay cancer development and progression."

Moreover, regarding the hugely important issue of restricting cancer stem cell expansion:

"Treatment of GB stem cell lines with a constant physiologic concentration of BHB (4 mmol/L), as seen in KD patients, resulted in reduction of clonogenic frequency and symmetrical stem cell divisions, suggesting that elevated ketones affect the putative cancer stem cell population."

Effective for diverse malignancies

Because a dependence on glycolysis is characteristic of all cancers these principles can be broadly applied.

"The combination of reduced glucose and increased ketone bodies has shown an enhanced anticancer effect...The KD mimics these biologic effects and has been proposed as a treatment for GB and other cancers...numerous groups have investigated the antitumor efficacy of a KD and an RKD in several types of cancer. RKD in experimental mouse models of glioma has been shown to be antitumorigenic, antiangiogenic, and pro survival, while also being anti-invasive, anti-inflammatory, and proapoptic by targeting signaling pathways related to glucose and glutamine metabolism. In animal models, feeding with the KD ad libitum has been reported to increase survival and reduce tumor growth. Other preclinical animal models such as gastric cancer, colon cancer, and metastatic cancer have used the KD, reporting similar antitumorigenic effects."

Effects on the mTOR pathway is especially important:

"The mTOR pathway is one of the largest and most utilized pathways in cellular signaling, with two complexes (mTORC1/mTORC2) that have demonstrated a role in tumorigenesis. Recently, it's been shown that inhibition of both mTORC1/mTORC2 signaling results in dramatically reduced cell viability in glioma cell lines, as well as inhibition of tumor growth in vivo. In our assessment of the sHFLC diet's effects on the mTOR pathway, we found significant reduction in both mTORC1/mTORC2 signaling...Taken together, these findings indicate that inhibition of the mTORC1/2 pathway can be achieved through dietary intervention, resulting in a potent anti-cancer treatment."

The authors conclusions highlight fundamental concerns in case management:

"Our work demonstrates that there is a distinct relationship between metabolism and proliferation that can be exploited by changing the energy sources in the body. Further research into the biochemical reactions of metabolic intermediates may shed more light on how ketone bodies are differentially utilized by tumor cells, as the role of mitochondria in tumor propagation and carcinogenesis is multifaceted and incompletely understood. Nevertheless, we effectively show that a combination of low glucose and high ketones results in negative proliferative effects on gliomaspheres, which can be translated in vivo with the sHFLC diet. This diet reduces overall tumor burden and increases survival, equivalent to a strict 1:6 KD, and has a complete nutritional profile. Hence we propose that dietary therapy, such as the sHFLC diet, could be utilized in the management of GB."

The Warburg effect, foundation of the benefits of a low glycemic ketogenic diet

An excellent study published in the International Journal of Cancer documenting decreased tumor cell viability and prolonged survival with supplemental ketones includes a fine review of the Warburg effect.

 "A century ago, Otto Warburg discovered that cancer cells display a unique metabolic phenotype of lactate fermentation in the presence of oxygen. This phenotype, known as the Warburg effect, enables tumor visualization using fluorodeoxyglucose positron emission tomography (FDG-PET) scans owing to the elevated rate of glucose consumption in most cancers. Metabolic therapies can exploit this phenotype, offering novel therapeutic directions aside from the classically targeted cytotoxic and gene-based therapies. The Warburg effect exposes a fundamental weakness of cancer cells, reliance on excess glucose for survival and maximal proliferation. Fasting, calorie restriction (CR) and the carbohydrate-restricted ketogenic diet have been successfully used to limit glucose availability and slow cancer progression in a variety of animal models and human studies."

Importantly, the ketogenic effect is additive to the benefits of low glucose...

"Previously, the anticancer effects of these dietary manipulations have largely been attributed to decreased circulating blood glucose, which limits energy substrates for cancer cells. New evidence suggests, however, that the physiological state of ketosis and elevated circulating ketones also have anticancer effects."

Ketogenic effect may be primary

For anti-cancer effects elevated ketones may be even more important than low glucose.

"Recently, Fine et al. demonstrated that a carbohydrate-restricted ketogenic diet inhibited disease progression and promoted partial remission in patients with advanced metastatic cancers from various tissue origins. [10] On average, the patients did not exhibit a drop in glucose from baseline, suggesting that decreased glucose availability was not the sole or primary cause of efficacy. Interestingly, the study found that the most important factor dictating the patients' response to therapy was the degree of elevated ketosis from baseline. Indeed, a prominent metabolic shift to higher levels of ketosis correlated with reduced disease progression, stable disease or partial regression."

Cancer as a mitochondrial disorder

The metabolic theory of cancer (as opposed to the somatic mutation theory) posits mitochondrial dysfunction as an instigator in the shift of normal to cancer cells.

"Although ketone bodies are efficient energy substrates for healthy extrahepatic tissues, cancer cells cannot effectively use them for energy. Widespread mitochondrial pathology has been observed in most if not all tumors examined, including decreased mitochondrial number, abnormal ultrastructural morphology, mitochondrial swelling, abnormal fusion–fission, partial or total cristolysis, mtDNA mutations, altered mitochondrial membrane potential and abnormal mitochondrial enzyme presence or function, among others.These defects in mitochondrial structure and function impair respiratory capacity and force a reliance on substrate-level phosphorylation for survival. As ketone bodies are metabolized exclusively within the mitochondria, cancer cells with impaired mitochondrial function are unable to efficiently metabolize ketone bodies for energy. Indeed, unlike healthy cells, ketone bodies fail to rescue glioma cells from glucose withdrawal-induced death."

Ketone bodies oppose cancer in multiple ways

A ketogenic diet does more than just starve cancer cells...

1. "Ketone bodies inhibit glycolysis, thus decreasing the main pathway of energy production for cancer cells.
2. Cancer cells thrive in an environment of elevated reactive oxygen species (ROS) production but are very sensitive to even small changes in redox status. Ketones decrease mitochondrial ROS production and enhance endogenous antioxidant defenses in normal cells, but not in cancer cells. Ketone metabolism in healthy cells near the tumor may inhibit cancer cell growth by creating a less favorable redox environment for their survival.
3. Ketone bodies are transported into the cell through the monocarboxylate transporters (MCTs), which are also responsible for lactate export. It has been shown that inhibiting MCT1 activity or inhibiting lactate export from the cell dramatically decreases cancer cell growth and survival. Ketones may impair cancer cells indirectly by competitive inhibition of the MCTs, decreasing critical lactate export from the cell.
4. Recently, Verdin and coworkers demonstrated that βHB acts as an endogenous HDAC inhibitor at millimolar concentrations easily achieved through fasting, CR or ketone supplementation such as with a ketone ester (KE). Thus, ketone bodies may elicit their anticancer effects by altering the expression of oncogenes and tumor suppressor genes under control of the cancer epigenome."

"Clearly, ketone bodies exhibit several unique characteristics that support their use as a metabolic therapy for cancer."

Ketones oppose metastasis

Effectiveness against metastasis is critical for successful cancer therapy.

"The Warburg effect is especially prevalent in aggressive cancers and metastatic cells. Metastasis, the spreading of a primary tumor to distal locations, is the primary cause of cancer morbidity and mortality and is responsible for more than 90% of cancer-related deaths."

Ketones can be easily increased by diet and supplementation, so authors set out to investigate in vivo effectiveness:

"It is possible to raise blood ketone levels without the need for carbohydrate restriction by administering a source of supplemental ketones or ketone precursors. 1,3-Butanediol (BD) is a commercially available food additive and hypoglycemic agent that is converted to βHB by the liver. The KE [ketone ester] elevates both AcAc and βHB in a dose-dependent manner to levels beyond what can be achieved with the KD or therapeutic fasting. Oral administrations of BD and KE have been shown to elevate blood ketones for at least 240 min in rats. As ketone bodies appear to elicit anticancer effects, and metastasis is the most significant obstacle in the successful treatment of neoplasms, we tested the efficacy of ketone supplementation in the VM-M3 cell line and mouse model of metastatic cancer."

They measured proliferation and viability in highly metastatic cells cultured in the presence and absence of β-hydroxybutyrate (βHB). Also adult male inbred VM mice were implanted subcutaneously with firefly luciferase-tagged syngeneic VM-M3 cells and fed a standard diet supplemented with either 1,3-butanediol (BD) or a ketone ester (KE) which are metabolized into βHB and acetoacetate. They then monitored tumor growth in vivo bioluminescent imaging, and documented Survival time, tumor growth rate, blood glucose, blood βHB and body weight.

Ketone supplementation prolonged survival and reduced tumor burden

The results were amazing, even without reducing glucose and calorie restriction:

"Ketone supplementation decreased proliferation and viability of the VM-M3 cells grown in vitro, even in the presence of high glucose. Dietary ketone supplementation with BD and KE prolonged survival in VM-M3 mice with systemic metastatic cancer by 51 and 69%, respectively (p < 0.05). Ketone administration elicited anticancer effects in vitro and in vivo independent of glucose levels or calorie restriction."

The authors discuss the profound clinical implications:

"The Warburg effect is the most ubiquitous cancer phenotype, exhibited by most if not all cancer types. Exploiting the metabolic deficiencies of cancer cells should be prioritized, because this therapeutic strategy would likely prove effective against most cancers. Mitochondrial dysfunction underlies many aspects of cancer metabolic deficiency and prevents cancer cells from effectively using ketone bodies for energy. In our study, ketone supplementation decreased VM-M3 cell proliferation and viability, confirming similar results demonstrated in other cancer types in vitro. Therefore, we hypothesized that dietary administration of ketone body precursors would inhibit disease progression in vivo. Indeed, dietary administration of ketone precursors, BD and KE, increased mean survival time by 51 and 69%, respectively, in VM-M3 mice with metastatic cancer. These data support the use of supplemental ketone administration as a feasible and efficacious cancer therapy, which should be further investigated..."

Although carbohydrate restriction has other important metabolic benefits, ketone supplementation was effective in prolonging survival even without it.

"Ketone supplementation decreased blood glucose after acute administration, decreased body weight with chronic administration and sustained ketosis in vivo, even when administered with a high-carbohydrate rodent chow in both healthy (VM/Dk) and cancer (VM-M3) mice. Our study demonstrates the ability of dietary administration of BD and KE to significantly elevate ketone bodiesin vivo for at least 12 hr in healthy VM/Dk mice and 7 days in VM-M3 cancer mice."

Moreover, ketone supplementation on its own reduces weight, diminishes appetite and improves insulin sensitivity.

"It is important to note that the metabolic changes associated with acute and chronic ketosis are vast and can dramatically affect blood metabolite concentrations. In previous studies, chronic BD and βHB administration has been shown to decrease food intake in the rat and pigmy goat. Similarly, Veech and coworkers demonstrated that feeding a KE-supplemented diet increased malonyl-CoA, an anorexigenic metabolite known to decrease food intake. Ketone-induced appetite suppression may account for the decreased blood glucose and body weight seen in treated VM-M3 cancer mice. Additionally, prior studies suggest that ketones increase insulin sensitivity, which may be contributing to the decreased circulating blood glucose in KE-fed mice...Furthermore, chronic ketosis enhances ketone utilization by tissues, known as keto-adaptation, resulting in lower blood ketone concentrations."

A ketogenic high fat diet with ketone supplementation may be more effective than calorie restriction

In the past, dietary treatment in cancer has emphasized carbohydrate or calorie restriction to exploit the Warburg effect, but this may not be the best approach.

"Interestingly, although CR [calorie restriction] decreased blood glucose and elevated blood ketones, CR mice exhibited a trend of increased latency to disease progression and increased survival that was not statistically significant from controls in our study. As described, some data suggest that elevated ketones are responsible for much of the anticancer efficacy of the ketogenic diet.Perhaps elevating ketones with exogenous sources such as ketone supplementation or a ketogenic diet, rather than elevating ketones endogenously through lipolysis such as occurs with CR, provides a more effective anticancer strategy. Additionally, ketone supplementation may preserve lean muscle mass to a greater degree than CR, and may therefore support overall health of the organism in this way...These data support the in vitro and in vivo conclusions of Fine et al. suggesting that ketone bodies can inhibit cancer progression independently of other factors such as carbohydrate restriction or CR."

Enhancement of radiation and chemotherapy

Ketogenic diet and ketone supplementation can enhance the cytotoxic effects of the increase in ROS (reactive oxygen species) by radiation and chemotherapy.

"The ketogenic diet has been shown to enhance the efficacy of both radiation and chemotherapy in vivo. As supplemental ketones mimic the physiological ketosis induced by the ketogenic diet, combining supplemental ketone therapy with standard of care could produce similar effects, even if administered with a SD [standard diet]. Furthermore, the neuroprotective effects of ketone metabolism have been widely documented. Ketone metabolism protects normal cells from oxidative damage by decreasing mitochondrial ROS production and enhancing endogenous antioxidant defenses. Radiation and chemotherapy work in large part by inducing ROS production in the tumor, but simultaneously incur damage to normal tissue. Ketone metabolism by healthy tissue would likely mitigate some of the adverse side effects of standard of care as ketones have been shown to protect against oxidative stress."

The authors' conclusion needs to be appreciated by any practitioner involvement in cancer case management:

"Our data strongly suggest that supplemental ketone administration could provide a safe, feasible and cost-effective adjuvant to standard care that should be further investigated in preclinical and clinical settings."

Exploiting Cancer Metabolism with Ketosis—Dr. Angela Poff

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