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"Warburg effect" (/ˈvɑːrbʊərɡ/) describes two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.

Contents

Plant physiologyEdit

In plant physiology, the Warburg effect is the decrease in the rate of photosynthesis by high oxygen concentrations.[1][2] Oxygen is a competitive inhibitor of carbon dioxide fixation by RuBisCO which initiates photosynthesis. Furthermore, oxygen stimulates photorespiration which reduces photosynthetic output. These two mechanisms working together are responsible for the Warburg effect.[3]

OncologyEdit

BasisEdit

Normal cells primarily produce energy through mitochondrial 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. This is called aerobic glycolysis, also termed the Warburg effect.[4] Aerobic glycolysis is less efficient than oxidative phosphorylation in terms of adenosine triphosphate production, but leads to the increased generation of additional metabolites that may particularly benefit proliferating cells.[4]

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.[5]

Diagnostically the Warburg effect is the basis for the PET scan in which an injected radioactive glucose analog is detected at higher concentrations in malignant cancers than in other tissues.[6]

Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,[7] 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.[8][9]

Possible explanationsEdit

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, which are involved in the cell's apoptosis program that kills cancer cells. It may also be an effect associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation, cancer cells (and normal proliferating cells) have been proposed to need to activate glycolysis, despite the presence of oxygen, to proliferate.[10] Evidence attributes some of the high anaerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase[11] responsible for driving the high glycolytic activity. In kidney cancer, this effect could be due to the presence of mutations in the von Hippel–Lindau tumor suppressor gene upregulating glycolytic enzymes, including the M2 splice isoform of pyruvate kinase.[12] TP53 mutation hits energy metabolism and increases glycolysis in breast cancer.[13]

The Warburg effect is associated with glucose uptake and utilization as this ties into how mitochondrial activity is regulated. The concern lies less in mitochondrial damage and more in the change in activity. On the other hand, tumor cells exhibit increased rates of glycolysis which can be explained with mitochondrial damage.[14]

In March 2008, Lewis C. Cantley and colleagues announced that the tumor M2-PK, a form of the pyruvate kinase enzyme, gives rise to 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; but PKM2 was identified in all of the cancer cells they had tested. This enzyme form 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.[15][16]

Glycolytic inhibitorsEdit

Many substances have been developed which inhibit glycolysis, and such inhibitors are currently the subject of intense research 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). 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 cancers.[25][26]


Pyruvate dehydrogenase plays a key role in 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. The activity of DCA is integral in the reduced expression of the kinases, preventing the inactivation of the PDC, allowing the conversion of pyruvate to acetyl-CoA rather than lactate through anaerobic respiration, permitting cellular respiration to continue. Through this mechanism of action, DCA works to counteract the increased production of lactate exhibited by tumor cells, by activating the pathway to pull the intermediates into the TCA cycle and finish off with oxidative phosphorylation. [27] The use of DCA as a sole cancer treatment has not been done yet seeing that research on the clinical activity of the drug is still ongoing, but in clinical trials conducted, it has been shown to be most effective when used with other cancer treatments. The neurotoxicity and pharmacokinetics of the drug still need to be monitored but seeing that it is a generic drug with a relatively small structure makes it cost-effective in the cancer therapy market. [28]


Blood glucose levels

High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose deprivation has led to apoptosis. These findings have initiated further study of the effects of carbohydrate restriction on tumor growth. Clinical evidence shows that lower blood glucose levels in late-stage cancer patients have been correlated with better outcomes.[29]

Alternative modelsEdit

A model called the "reverse Warburg effect" describes cells producing energy by glycolysis, but which are not tumor cells, but stromal fibroblasts.[30] In this scenario, the stroma become corrupted by cancer cells and turn into factories for the synthesis of energy rich nutrients. The cells then take these energy rich nutrients and use them for TCA cycle which is used for oxidative phosphorylation. This results in an energy rich environment that allows for replication of the cancer cells. This still supports Warburg's original observation that tumors show a tendency to create energy through aerobic glycolysis. [31]

Cancer metabolism and epigeneticsEdit

Nutrient utilization 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 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 suggest that metabolic alterations may affect the epigenome. Understanding the relation between metabolism and epigenetics in cancer cells may open new avenues for anti-cancer strategies.[32]

Drug researchEdit

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 which have therapeutic benefit.[33]

History of Otto WarburgEdit

Around the 1920s, Otto Warburg and his group of colleagues were able to conclude that by depriving tumor cells of glucose and oxygen, they would be able to deprive tumor cells of energy. By depriving the tumor cells of energy, this is how they would kill the tumor cell. Another biochemist name Herbert Crabtree further extended Warburg's research by discovering that perhaps because of environmental or genetic influence, there is variability in fermentation as well as aerobic glycolysis. Warburg also hypothesized that dysfunctional mitochondria was the source of anaerobic glycolysis, which he also hypothesized was the source of cancer.[5]

ReferencesEdit

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