Warburg effect (oncology)

Around the 1920s, Otto Heinrich Warburg and his group concluded that deprivation of glucose and oxygen in tumor cells leads to a lack of energy, resulting in cell death. Biochemist Herbert Grace Crabtree further extended Warburg's research by discovering environmental or genetic influences. Crabtree observed that yeast, Saccharomyces cerevisiae, prefer fermentation leading to ethanol production over aerobic respiration, in aerobic conditions and in the presence of a high concentration of glucose - the Crabtree effect. Warburg observed a similar phenomenon in tumors - cancer cells tend to use fermentation for obtaining energy even in aerobic conditions - coining the term "aerobic glycolysis". The phenomenon was later termed Warburg effect after its discoverer.[6] Warburg hypothesized that dysfunctional mitochondria may be the cause of the higher rate of glycolysis seen in tumor cells, as well as a predominant cause of cancer development.[7]

Normal cells primarily produce energy through glycolysis followed by mitochondrial citric acid cycle and oxidative phosphorylation. However, most cancer cells predominantly produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Anaerobic glycolysis is less efficient than oxidative phosphorylation for producing adenosine triphosphate and leads to the increased generation of additional metabolites that may particularly benefit proliferating cells.[6] The Warburg effect has been much studied, but its precise nature remains unclear, which hampers the beginning of any work that would explore its therapeutic potential.[7]

Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,[8] a claim now known as the Warburg hypothesis. Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a cause.[9][10]

Older hypotheses such as the Warburg hypothesis suggest the Warburg effect may simply be a consequence of damage to the mitochondria in cancer. It may also be an adaptation to low-oxygen environments within tumors, or a result of cancer genes shutting down the mitochondria, which are involved in the cell's apoptosis program that kills cancer cells.

As of 2013, scientists had been investigating the possibility of therapeutic value presented by the Warburg effect. The increase in nutrient uptake by cancer cells has been considered as a possible treatment target by exploitation of a critical proliferation tool in cancer, but it remains unclear whether this can lead to the development of drugs that have therapeutic benefit.[16] Many substances have been developed which inhibit glycolysis and so have potential as anticancer agents,[17] including SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3-BrPA, bromopyruvic acid, or bromopyruvate), 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), 5-thioglucose and dichloroacetic acid (DCA).

A clinical trial for 2-DG [2008] showed slow accrual and was terminated.[18] There is no evidence yet [2012] to support the use of DCA for cancer treatment.[19]

Alpha-cyano-4-hydroxycinnamic acid (ACCA;CHC), a small-molecule inhibitor of monocarboxylate transporters (MCTs; which prevent lactic acid build up in tumors) has been successfully used as a metabolic target in brain tumor pre-clinical research.[20][21][22][23] Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.[24]

Dichloroacetic acid (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 cancer.[25][26]

Pyruvate dehydrogenase catalyses the rate-limiting step in the aerobic oxidation of glucose and pyruvate and links glycolysis to the tricarboxylic acid cycle (TCA). DCA acts a structural analog of pyruvate and activates the pyruvate dehydrogenase complex (PDC) to inhibit pyruvate dehydrogenase kinases, to keep the complex in its un-phosphorylated form. DCA reduces expression of the kinases, preventing the inactivation of the PDC, and allowing the conversion of pyruvate to acetyl-CoA rather than lactate through anaerobic respiration, thereby permitting cellular respiration to continue. Through this mechanism of action, DCA works to counteract the increased production of lactate exhibited by tumor cells by enabling the TCA cycle to metabolize it by oxidative phosphorylation.[27] DCA has not been evaluated as a sole cancer treatment yet, as research on the clinical activity of the drug is still in progress, but it has been shown to be effective when used with other cancer treatments. The neurotoxicity and pharmacokinetics of the drug still need to be monitored but if its evaluations are satisfactory it could be very useful as it is an inexpensive small molecule.[28]

Lewis C. Cantley and colleagues found that tumor M2-PK, a form of the pyruvate kinase enzyme, promotes the Warburg effect. Tumor M2-PK is produced in all rapidly dividing cells and is responsible for enabling cancer cells to consume glucose at an accelerated rate; on forcing the cells to switch to pyruvate kinase's alternative form by inhibiting the production of tumor M2-PK, their growth was curbed. 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 tested. This enzyme form is not usually found in quiescent tissue, though it is apparently necessary when cells need to multiply quickly, e.g., in healing wounds or hematopoiesis.[29][30]

Nutrient use is dramatically altered when cells receive signals to proliferate. Characteristic metabolic changes enable cells to meet the large biosynthetic demands associated with cell growth and division. Changes in rate-limiting glycolytic enzymes redirect metabolism to support growth and proliferation. Metabolic reprogramming in cancer is largely due to the oncogenic activation of signal transduction pathways and transcription factors. Although less well understood, epigenetic mechanisms also contribute to the regulation of metabolic gene expression in cancer. Reciprocally, accumulating evidence suggests that metabolic alterations may affect the epigenome. Understanding the relationship between metabolism and epigenetics in cancer cells may open new avenues for anti-cancer strategies.[34]

A rapid increase in metabolism is needed during the activation of T lymphocytes, which reside in peripheral blood containing stable concentrations of glucose. As glucose is plentiful, T-cells are able to switch to fast use of glucose using the coreceptor CD28.[35] This CD3/CD28 signaling parallels insulin signaling, as both lead to higher expression of glucose transporter 1 (Glut-1) on the cell surface via the activation of Akt kinase. CD28 signal transduction not only leads to higher glucose uptake but also to an increased rate of glycolysis. Most of the glucose taken up by activated T lymphocytes is metabolised to lactate and dumped out of the cells.[36]

• Oncometabolism
• Overflow metabolism