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The phrase "Warburg effect" is used for two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.

Physiology

In plant physiology, the Warburg effect is the inhibition of carbon dioxide fixation, and subsequently of photosynthesis, by high oxygen concentrations. The oxygenase activity of RuBisCO, which initiates the process of photorespiration, largely accounts for this effect.

Oncology

Basis

In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by glycolysis followed by lactic acid fermentation in the cytosol, rather than by oxidation of pyruvate in mitochondria like most normal cells. This occurs even if oxygen is plentiful. Otto Warburg postulated that this change in metabolism is the fundamental cause of cancer, a claim now known as the Warburg hypothesis. Today it is known that mutations in oncogenes and tumor suppressor genes are the fundamental cause of cancer. The Warburg effect may simply be a consequence of damage to the mitochondria in cancer, or an adaptation to low-oxygen environments within tumors, or a result of cancer genes shutting down the mitochondria because they are involved in the cell's apoptosis program which would otherwise kill cancerous cells. The Warburg effect may also be an effect associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation, it has been proposed that cancer cells (and normal proliferating cells) may need to activate glycolysis despite the presence of oxygen in order to proliferate .

Role in cancer

On 16 March 2008 it was reported that Harvard Medical School announced that they had identified the enzyme that gave rise to the Warburg Effect.

HMS researchers stated that pyruvate kinase M2, an enzyme variety produced in all rapidly-dividing cells, was responsible for enabling cancer cells to consume glucose at an accelerated rate, and on forcing the cells to switch to pyruvate kinase's alternative form by inhibiting the production of Tumor M2-PK, their growth was curbed. They also demonstrated that on introducing the cells to laboratory mice, their ability to develop tumours was severely compromised. The researchers acknowledged the fact that the exact chemistry of glucose metabolism was likely to vary across different forms of cancer, however PKM2 was identified in all of the cancer cells they had experimented upon. The enzyme variety is not usually found in healthy tissue, though it is apparently necessary when cells need to multiply quickly, e.g. in healing wounds or hematopoiesis.

Glycolytic Inhibitors

Many substances have been developed which inhibit glycolysis, and such glycolytic inhibitors are currently the subject of intense research as anticancer agents. Some glycolytic inhibitors currently being studied as anticancer treatments include SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3-BrPA, Bromopyruvic acid, or bromopyruvate), 3-BrOP, 5-thioglucose and dichloroacetic acid (DCA).

DCA, a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase, downregulates glycolysis in vitro and in vivo. Researchers at the University of Alberta theorized in 2007 that DCA might have therapeutic benefits against many types of cancers. As a result, human clinical trials began in 2007.

DCA is generally well-tolerated, even in children. However, at sustained, higher doses (generally 25 mg/kg/day taken orally, or greater), there is increased risk of several reversible toxicities, especially peripheral neuropathy, neurotoxicity, and gait disturbance. Peripheral neuropathy may be ameliorated or prevented with thiamine (vitamin B1) supplementation.

Short-term, infused, bolus doses of DCA at 50 mg/kg/day have been well-tolerated. Long term use (a year or more) of high doses of DCA has been shown to increase risk of liver cancer in mice, however the dosages required for carcinogenicity (> 77 mg/kg/day) are significantly higher than suggested therapeutic doses in humans.

References

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12. Pearson H (2008). "Role of dichloroacetate in the treatment of genetic mitochondrial diseases". Adv Drug Deliv Rev. 60 (13, 14): 1478–1487. doi:10.1016/j.addr.2008.02.014. PMID 18647626.
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• Photosynthesis
• Oncology