Warburg Effect And Some Possible Cancer Treatments

The Warburg effect is important in cancer, since cancer cells rely more heavily than do normal cells on glycolysis for energy production.  This may point at therapies targeting this effect for patient benefit.  A paper is here, abstract:

As stated by Otto Warburg nearly a century ago, cancer is a metabolic disease, a fermentation caused by malfunctioning mitochondria, resulting in increased anabolism and decreased catabolism. Treatment should, therefore, aim at restoring the energy yield. To decrease anabolism, glucose uptake should be reduced (ketogenic diet). To increase catabolism, the oxidative phosphorylation should be restored. Treatment with a combination of α-lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models. This treatment, in combination with conventional chemotherapy, has yielded extremely encouraging results in glioblastoma, brain metastasis and lung cancer. Randomized trials are necessary to confirm these preliminary data. The major limitation is the fact that the combination of α-lipoic acid and hydroxycitrate can only be effective if the mitochondria are still present and/or functional. That may not be the case in the most aggressive tumors. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Concomitant correction of this alkalosis may be a very effective treatment in case of mitochondrial failure.

Note that a ketogenic diet is considered one mechanism whereby the Warburg effect can be leveraged for anti-cancer treatment.

Cancer Stem Cells And Lipid Metabolism

Cancer stem cells seem to have an increased reliance on lipid metabolism, which can be a target for anti-cancer therapy.  I wonder if this has any implications for a ketogenic (high-fat) diet for cancer?  On the one hand, most cancer cells seem “glucose-addicted” so a low-carb, high-fat diet may be preferable.  On the other hand, if cancer stem cells rely more on fat, then will increased dietary fat be a problem?  This question needs to be investigated.  Abstract:

BACKGROUND:

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a small population of cancer cells with self-renewal and tumor-initiating properties. Unlike the bulk of tumor cells, CSCs or TICs are refractory to traditional therapy and are responsible for relapse or disease recurrence in cancer patients. Stem cells have distinct metabolic properties compared to differentiated cells, and metabolic rewiring contributes to self-renewal and stemness maintenance in CSCs.

MAIN BODY:

Recent advances in metabolomic detection, particularly in hyperspectral-stimulated raman scattering microscopy, have expanded our knowledge of the contribution of lipid metabolism to the generation and maintenance of CSCs. Alterations in lipid uptake, de novo lipogenesis, lipid droplets, lipid desaturation, and fatty acid oxidation are all clearly implicated in CSCs regulation. Alterations on lipid metabolism not only satisfies the energy demands and biomass production of CSCs, but also contributes to the activation of several important oncogenic signaling pathways, including Wnt/β-catenin and Hippo/YAP signaling. In this review, we summarize the current progress in this attractive field and describe some recent therapeutic agents specifically targeting CSCs based on their modulation of lipid metabolism.

CONCLUSION:

Increased reliance on lipid metabolism makes it a promising therapeutic strategy to eliminate CSCs. Targeting key players of fatty acids metabolism shows promising to anti-CSCs and tumor prevention effects.

Aerobic Glycolysis In Amyotrophic Lateral Sclerosis And Huntington's Disease

In amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), there is upregulation of Wnt signaling and subsequent aberrant aerobic glycolysis (breakdown of glucose for energy).  This can be targeted for therapeutic interventions.  Abstract:

Neurodegenerative cells are the sites of numerous metabolic and energetic abnormalities with abnormalities in energy production. Energy is the primary determinant of neuronal viability. In neurodegenerative cells, metabolic enzymes are modified by the dysregulation of the canonical WNT/β-catenin pathway. In amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), WNT/β-catenin pathway is upregulated. We focused this review on the hypothesis of aerobic glycolysis stimulated by the upregulation of WNT/β-catenin pathway in ALS and HD. Upregulation of WNT/β-catenin pathway induces aerobic glycolysis, named Warburg effect, through activation of glucose transporter (Glut), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1 (PDK1), monocarboxylate lactate transporter 1 (MCT-1), lactate dehydrogenase kinase-A (LDH-A), and inactivation of pyruvate dehydrogenase complex (PDH). Aerobic glycolysis consists of a supply of a large part of glucose into lactate regardless of oxygen. Aerobic glycolysis is less efficient in terms of ATP production compared with oxidative phosphorylation because of the shunt of the TCA cycle. Dysregulation of energetic metabolism promotes cell death and disease progression in ALD and HD. Aerobic glycolysis regulation is an attractive mechanism for developing therapeutic interventions.

Starve Cancer To Death

This NY Times article discussing the Warburg effect is of interest.

The default approach of modern medicine will always be to find a pharmacological agent to target cancer metabolism. Nothing wrong with that per se, but diet is important as well. If doctors and oncology centers are going to offer their cancer patients glazed donuts and milk chocolates as snack food, they are defeating the purpose of treatments that aim at glucose-addicted tumors. 

Similarly, a diet high in refined carbohydrates, sugar, etc. is not "optimal" for cancer prevention.