Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

Abstract

Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

Keywords: fermentation; glutaminolysis; glycolysis; inflammation; metastasis; non-toxic; survival.

Figure 1

Electron microscopy of primary breast cancer cells (human mammary carcinoma HMC-1) and human epithelial mammary cell control line (HEMC). Abnormal mitochondrial morphology in the HMC-1 cell showing loss of invaginations and vacuoles. These abnormalities in mitochondria ultrastructure were linked to abnormalities in the electron transport chain and are in general agreement with those from other studies of breast cancer mitochondria (37, 40, 42). Reprinted with permission from Putignani et al. (43).

Figure 2

The glutaminolysis pathway. The succinyl-CoA ligase reaction, metabolizing succinyl-CoA to succinate, produces high-energy phosphates (ATP) in the absence of oxidative phosphorylation through the process of substrate-level phosphorylation in the mitochondrial matrix. Provision of succinyl-CoA by the α-ketoglutarate dehydrogenase complex is crucial for maintaining the function of succinyl-CoA ligase thus preventing the adenine nucleotide translocase from reversing. Succinate contributes to inflammation and stabilizes Hif-1a, a key transcription factor that contributes to the aerobic fermentation (–56).

Figure 3

Linkage of plasma glucose and ketone body levels to cancer management. The glucose and ketone (beta-hydroxybutyrate) values are within normal physiological ranges for humans that are under water-only fasting. This state is considered the zone of metabolic management for most cancers. The zone of metabolic management is obtained gradually, as circulating levels of glucose fall and ketones rise. the Glucose Ketone Index (GKI) tracks the transition to therapeutic ketosis. The dashed lines highlight individual variability that could exist in reaching a therapeutic GKI. GKI values approaching 1.0 and below are considered potentially therapeutic. [Reprinted from Meidenbauer et al. (197), and distributed under a Creative Commons license].

Figure 4

Tracking an individual's GKI using the Glucose Ketone Index Calculator. Index values of 1.0 or below are considered best for managing cancer growth. Individual glucose and ketone values are shown, along with the corresponding GKI values. The GKI values are plotted over the course of a month, whereas the target GKI value (1.0) is plotted as a single line. Tumor management is predicted to be better (slower growth) within the metabolic target zone than outside of the zone. [Reprinted from Meidenbauer et al. (197), and distributed under a Creative Commons license].

Figure 5

Breast Cancer Management with Press-Pulse Therapeutic Strategy. Arens and West considered the simultaneous occurrence of “Press-Pulse” disturbances as the mechanism responsible for the mass extinction of organic populations during prior evolutionary epochs (213). We described how this concept could be adopted as a therapeutic strategy for the management and possible eradication of cancer (34). This therapeutic strategy considers all cancer, including breast cancer, as a single disease that can be managed by transitioning the energy metabolism of normal cells from glucose to non-fermentable ketone bodies, while simultaneously restricting the availability of fermentable fuels (glucose and glutamine) to tumor cells (34). The reduction in blood glucose levels will also reduce insulin and insulin-like growth factor 1, which are known to drive rapid tumor growth (184, 214, 215). This metabolic therapeutic strategy exploits the dependency of tumor cells on glucose and glutamine fermentation and their inability to metabolize ketone bodies for energy due to defects in the number, structure and function of the tumor mitochondria. In essence, the press-pulse therapy pits the metabolic demands of the mutated tumor cells against those of the normal cells, which evolved to adapt and survive under the extremes of nutrient stress (216). Collections of random mutations will prevent tumor cells from adapting to nutrient stress, thus leading to their extinction according to evolutionary theory (81). As a cancer diagnosis can increase emotional stress and blood glucose, stress management techniques together with exercise could improve general health while reducing glucose availability to the tumor. The press therapies would work synergistically with acute pulse therapies to further restrict glucose and glutamine metabolism. HBOT would work synergistically with the press therapies to increase oxidative stress selectively in tumor cells. The timing (spacing) between the various pulse therapies is designed to stress tumor cell metabolism while minimizing toxicity to normal body cells (34). This therapeutic strategy will target the fermentation metabolism common to most breast tumor cells, thus degrading tumor burden gradually with little or no toxicity. The color change from red (diseased with darker red spots indicative of metastatic lesions), to yellow (with reduced metastasis), to green (resolution) in the Vitruvian man indicates the gradual metabolic management and possible resolution of the breast cancer. The pill and Rx symbols are suggestive of drugs taken orally and/or intravenously (prescription) that would be effective in targeting simultaneously glycolysis and glutaminolysis. Pulse therapies would be eliminated with evidence of tumor management or resolution, while press therapies could continue under modifications or adjustments (arrow). Optimization of timing, dosing, and scheduling of the press-pulse treatments will facilitate eradication of tumor cells with minimal patient toxicity. This therapeutic strategy is a framework for future clinical trials. HBOT, hyperbaric oxygen therapy; KD-R, calorie restricted ketogenic diet. The figure is reprinted with modifications, as described previously (34) and distributed under a Creative Commons license.