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.

Impact of a ketogenic diet intervention during radiotherapy on body composition: III—final results of the KETOCOMP study for breast cancer patients

“…This analysis focused on the primary study outcome of body composition changes. Another potential benefit of a KD during radiotherapy that is mainly supported by preclinical data could be a synergistic anti-tumor effect mediated through the ketogenic state and its effect on a variety of molecular signaling pathways [47][48][49][50][51]. A randomized controlled trial conducted by Khodabakhshi and colleagues found an overall survival benefit (p = 0.046) for 25 locally advanced or metastatic breast cancer patients eating a KD during neoadjuvant chemotherapy compared to 18 control patients who received chemotherapy without dietary intervention [52].…”

On the Origin of ATP Synthesis in Cancer

“…ROS production is also greater in cancer cells than in normal cells (Chen et al, 2016 iScience Review 2015). The genomic instability and random somatic mutations seen in most cancers arise largely as downstream epiphenomenon of ROS production and OxPhos dysfunction (Fosslien, 2008;Bartesaghi et al, 2015;Galadari et al, 2017;Desler et al, 2010;Degtyareva et al, 2013;Seyfried et al, 2020). Furthermore, mitochondrial oxygen consumption increases, rather than decreases, during the S phase of the cell cycle in some cancer cells without generation of ATP further indicating that oxygen consumption was not connected to ATP synthesis through OxPhos (Olivotto et al, 1984).…”

“…Genomic instability and somatic mutations would arise as a consequence of protracted mitochondrial ROS production together with acidification of extracellular microenvironment (Seyfried et al, 2014). Metastasis arises from respiratory damage in cells of myeloid/macrophage origin that would use glutamine as a major fuel for ATP synthesis (Seyfried and Huysentruyt, 2013;Seyfried et al, 2020). The degree of tumor progression and malignancy can be linked directly to the energy transition from OxPhos to SLP.…”

“…Although some gene mutations can cause abnormalities in mitochondrial structure and function, mitochondrial abnormalities can also arise independently of gene mutations (Seyfried et al, 2020;Seyfried, 2012a). Proton leak and uncoupling, which diminish respiratory efficiency (Brand and Nicholls, 2011), are also greater in tumor cells than in normal cells (Seyfried, 2012e, Villalobo andLehninger, 1979;Lemarie and Grimm, 2011).…”

Promising Effect of a New Ketogenic Diet Regimen in Patients with Advanced Cancer

“…The ketogenic diet is said to affect glucose metabolism [25] and gene expression [26,27] because of changes in the metabolic environment and ketone bodies acting as signal molecules [28]. The term "ketogenic metabolic therapy" has also been proposed from the ketogenic diet [29,30]. In the present study, blood glucose and insulin levels were significantly decreased, suggesting that the ketogenic diet directly affects the insulin/IGF-1 signaling pathway and PI3K activity.…”