Revisiting the Warburg Effect: Diet-Based Strategies for Cancer Prevention

Abstract

It is widely acknowledged that cancer cell energy metabolism relies mainly on anaerobic glycolysis; this phenomenon is described as the Warburg effect. However, whether the Warburg effect is caused by genetic dysregulation in cancer or is the cause of cancer remains unknown. The exact reasons and physiology of this abnormal metabolism are unclear; therefore, many researchers have attempted to reduce malignant cell growth in tumors in preclinical and clinical studies. Anticancer strategies based on the Warburg effect have involved the use of drug compounds and dietary changes. We recently reviewed applications of the Warburg effect to understand the benefits of this unusual cancer-related metabolism. In the current article, we summarize diet strategies for cancer treatment based on the Warburg effect.

Figure 1

Principles of calorie restriction (CR) and ketogenic diet (KD) in cancer therapy by targeting the Warburg effect. Metabolic differences of normal cells versus cancer cells. (a) In normal cells, once glucose is uptaken into the cells by GLUT, it subsequently enters the glycolysis, generating ATP and pyruvate. The pyruvate then entered the mitochondria and is catalyzed to acetyl-CoA, a substrate of the TCA cycle. Products from the TCA cycle provide substrates for OXPHOS complexes thereby providing a necessary ATP amount via ATP synthase (complex V). (b) In case of normal cells feeding into CR or KD, glucose lever is low, and the glycolysis and ATP from this process are prevented. However, the enhancement of ketone level by CR or KD could still stabilize acetyl-coA level in the mitochondria thus compensating the needed ATP. (c) As mentioned in the Warburg theory, cancer cells trigger large glucose uptake and glycolysis, which provide enough ATP, nucleotide, and lactic acid for cancer growth. (d) CR and KD abolish glycolysis, resulting in reduced needed biomass materials such as nucleotide and microenvironment such as lactic acid. Moreover, mitochondrial dysfunction and lack of mitochondrial necessary enzymes metabolizing ketone bodies to acetyl-coA cause the mitochondria to not generate to compensate for ATP. Thus, cancer could not proliferate probably. Taken together, using CR or KD can specifically target cancer growth. (Thin arrows represent normal stimulation/activation; thick arrows represent overstimulation/activation).