Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?

Seyfried, Thomas N.; Shelton, Laura M.; Arismendi-Morillo, Gabriel; Kalamian, Miriam; Elsakka, Ahmed M.; Maroon, Joseph C.; Mukherjee, Purna

doi:10.1007/s11064-019-02795-4

Cited by 41 publications

(66 citation statements)

References 165 publications

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“…Cells do not make choices or have preferences, but simply respond to conditions in their internal and external environments according to evolutionarily designed metabolic programs. As proliferation, rather than quiescence, is the default state of metazoan cells (8,82), unbridled proliferation becomes the consequence when fermentation gradually replaces respiration in cancer cells (21,83,84). Indeed, unbridled proliferation was the dominant growth phenotype of all organisms that existed on the planet before oxygen entered the atmosphere some 2.5 billion years ago (83).…”

Section: Glutaminolysismentioning

confidence: 99%

“…In other words, the mutations seen in tumor cells arise as a consequence of impaired energy metabolism (32,64). Oncogenes such as Hif-1alpha, Myc, Ras, BRAF, etc., facilitate the dependence of tumor cells on glucose and glutamine while defects in the tumor suppressor genes p53 and pRb will compromise OxPhos function thus causing further dependency on fermentation for growth (28,46,84,(94)(95)(96)(97)(98)(99). These genes mutations are linked to breast cancer and other cancers through mitochondrial dysfunction.…”

Section: Role Of Reactive Oxygen Species (Ros) and Oncogenes In The Omentioning

confidence: 99%

“…mSLP will provide ATP for F1-F0-ATP synthase in an effort to maintain a moderate mitochondrial membrane potential and prevent reversal. Based on the foundational biological principle that structure determines function (43,168,177,178), ketone bodies and fatty acids cannot serve as major respiratory fuels for tumor cells containing defects in mitochondrial structure and function (46,84). Hence, it would be helpful to include evidence of normal mitochondria ultrastructure and electron transport chain activities in reports indicating that ketone bodies and fatty acids are fuels for OxPhos-generated ATP synthesis in cancer cells.…”

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

“…The microenvironment of many tumors is hypoxic, acidotic, and enriched with glucose and glutamine. Under KMT, this pro-tumorigenic microenvironment becomes less inflamed (84,182,183). Restricted KDs and calorie restriction are antiinvasive, antiangiogenic, anti-inflammatory, and capable of killing tumor cells through a pro-apoptotic mechanism (181)(182)(183)(184)(185)(186)(187)(188).…”

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

“…However, therapeutic GKI values can be difficult to achieve for many cancer patients. For example, tumor burden, toxic treatment protocols, and emotional and physical stress can combine to elevate blood glucose and insulin levels thus preventing the patient from achieving therapeutic GKI values (34, 84,210). Further refinement of existing KMT therapies along with introduction of new therapies may serve to mitigate this obstacle.…”

Section: The Glucose Ketone Indexmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Glutaminolysismentioning

confidence: 99%

Section: Role Of Reactive Oxygen Species (Ros) and Oncogenes In The Omentioning

confidence: 99%

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

Section: The Glucose Ketone Indexmentioning

confidence: 99%

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

et al. 2020

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The Potential of the Gut Microbiome to Reshape the Cancer Therapy Paradigm

Liu

Shah

2022

JAMA Oncol

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This review aims to highlight the current understanding of the association of the gut microbiome with the therapeutic response to immunotherapy, chemotherapy, radiotherapy, cancer surgery, and more, while also contextualizing possible synergistic strategies with the microbiome for tackling some of the most challenging tumors. It also provides insights on contemporary methods that target the microbiota and the current progression of findings being translated from bench to bedside. CONCLUSIONS AND RELEVANCEUltimately, the importance of gut bacteria in cancer therapy cannot be overstated in its potential for ushering in a new era of cancer treatments. With the understanding that the microbiome may play critical roles in the tumor microenvironment, holistic approaches that integrate microbiome-modulating treatments with biological, immune, cell-based, and surgical cancer therapies should be explored.

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Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity

et al. 2020

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While pregnancy may accelerate glioblastoma multiforme (GBM) growth, parity and progesterone (P4) containing treatments (ie, hormone replacement therapy) reduce the risk of GBM development. In parallel, low and high doses of P4 exert stimulating and inhibitory actions on GBM growth, respectively. The mechanisms behind the high‐dose P4‐suppression of GBM growth is unknown. In the present study, we assessed the changes in growth and proteomic profiles when high‐dose P4 (100 and 300 µM) was administered in human U87 and A172 GBM cell lines. The xCELLigence system was used to examine cell growth when different concentrations of P4 (20, 50, 100, and 300 µM) was administered. The protein profiles were determined by two‐dimensional gel electrophoresis in both cell lines when 100 and 300 µM P4 were administered. Finally, the pathways enriched by the differentially expressed proteins were assessed using bioinformatic tools. Increasing doses of P4 blocked the growth of both GBM cells. We identified 26 and 51 differentially expressed proteins (fc > 2) in A172 and U87 cell lines treated with P4, respectively. Only the pro‐tumorigenic mitochondrial ornithine aminotransferase and anti‐apoptotic mitochondrial 60 kDa heat shock protein were downregulated in A172 cell line and U87 cell line when treated with P4, respectively. Detoxification of reactive oxygen species, cellular response to stress, glucose metabolism, and immunity‐related proteins were altered in P4‐treated GBM cell lines. The paradox on the effect of low and high doses of P4 on GBM growth is gaining attention. The mechanism related to the high dose of P4 on GBM growth can be explained by the alterations in detoxification mechanisms, stress, and immune response and glucose metabolism. P4 suppresses GBM growth and as it is nontoxic in comparison to classical chemotherapeutics, it can be used as a new strategy in GBM treatment in the future.

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Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?

Cited by 41 publications

References 165 publications

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

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

The Potential of the Gut Microbiome to Reshape the Cancer Therapy Paradigm

Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity

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