Warburg hypothesis

Warburg hypothesis

Warburg's hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg in 1924. [O. Warburg, K. Posener, E. Negelein: Ueber den Stoffwechsel der Tumoren; "Biochemische Zeitschrift", Vol. 152, pp. 319-344, 1924. de icon. Reprinted in English in the book "On metabolism of tumors" by O. Warburg, Publisher: Constable, London, 1930.] He hypothesized that cancer, malignant growth, and tumor growth are caused by the fact that tumor cells mainly generate energy (as e.g. adenosine triphosphate / ATP) by non-oxidative breakdown of glucose (a process called glycolysis). This is in contrast to "healthy" cells which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end-product of glycolysis, and is oxidized within the mitochondria. Hence, according to Warburg, cancer should be interpreted as a mitochondrial dysfunction. Warburg reported a fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect.

It is now known that cancer is caused by mutations in the genome of the cells in a process called malignant transformation, resulting in an uncontrolled growth of cells. [cite journal |author=Bertram JS |title=The molecular biology of cancer |journal=Mol. Aspects Med. |volume=21 |issue=6 |pages=167–223 |year=2000 |pmid=11173079 |doi=10.1016/S0098-2997(00)00007-8] [cite journal |author=Grandér D |title=How do mutated oncogenes and tumor suppressor genes cause cancer? |journal=Med. Oncol. |volume=15 |issue=1 |pages=20–6 |year=1998 |pmid=9643526 |doi=10.1007/BF02787340] The metabolic differences observed by Warburg are now thought to be an adaption of cancer cells to the hypoxic (oxygen-deficient) conditions inside solid tumors, and therefore not the cause, as he claimed, but an effect of cancer.

Warburg articulated his hypothesis in a paper entitled "The Prime Cause and Prevention of Cancer" which he presented in lecture at the meeting of the Nobel-Laureates on June 30, 1966 at Lindau, Lake Constance, Germany. In this speech, Warburg presented evidence in support of the claim that anaerobiosis was a primary cause of cancerous cells. Put in his own words, "the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar." [cite paper
title = The Prime Cause and Prevention of Cancer
version =
author = Otto Heinrich Warburg
date = June 30, 1966
url = http://healingtools.tripod.com/primecause1.html/
format =

In recent years, Warburg's hypothesis has re-gained attention due to several discoveries linking impaired mitochondrial function as well as impaired respiration to the growth, division and expansion of tumor cells. In a study by Michael Ristow and co-workers, colon cancer lines were modified to overexpress frataxin. The results of their work suggest that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals. [cite journal | title = Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. | author = Schulz TJ, Thierbach R, Voigt A, Drewes G, Mietzner B, Steinberg P, Pfeiffer AF, Ristow M. | journal = Journal of Biological Chemistry | volume = 281 | issue = 2 | pages = 977–981 | date = January 13, 2006 | doi = 10.1074/jbc.M511064200 | pmid = 16263703]

Subsequent work has shown that the Warburg effect, indeed, might lead to a promising approach in the treatment of solid tumors. The drug dichloroacetic acid, which promotes respiration and the activity of mitochondria, has been shown to kill cancer cells "in vitro" and in some animal models.cite journal |author=Bonnet S, Archer S, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee C, Lopaschuk G, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter C, Andrade M, Thebaud B, Michelakis E |title=A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth |journal=Cancer Cell |volume=11 |issue=1 |pages=37–51 |year=2007 |pmid=17222789 |doi=10.1016/j.ccr.2006.10.020] The body often kills damaged cells by apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells where the mitochondria are shut down. According to one hypothesis, the reactivation of mitochondria in cancer cells might also restart their apoptosis program. [cite news | author = Jerry Adler | publisher = Newsweek | date = 23 January 2007 | title = A New Way to Fight Cancer? | url = http://www.newsweek.com/id/70212] [Cite journal
issn = 0145479
volume = 39
issue = 1
pages = 1–12
last = Pedersen
first = Peter L
title = The cancer cell's "power plants" as promising therapeutic targets: an overview
journal = Journal of bioenergetics and biomembranes
date = 2007-02

See also

* Carcinogen
* 2-Deoxy-D-glucose
* Ketogenic diet
* Pyruvic acid
* Respiration


Further reading

* [http://www.nutritionandmetabolism.com/content/2/1/30 "Targeting energy metabolism in brain cancer: review and hypothesis,"] Thomas N Seyfried and Purna Mukherjee, Biology Department, Boston College, Chestnut Hill, MA 02467, USA
* [http://lib.bioinfo.pl/pmid:17879147 Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect"...] . Peter Pedersen, Johns Hopkins U., J Bioenerg Biomembr. 2007 Sep 19; : 17879147
* [http://acs.confex.com/acs/norm07/techprogram/P44814.HTM Glycolytic enzyme inhibitors as novel anti-cancer drugs] (3-bromopyruvate (3BP) and iodoacetate (IAA)), James C.K. Lai et al., Idaho State, June 2007
* [http://www.time.com/time/health/article/0,8599,1662484,00.html Can a High-Fat Diet Beat Cancer?] by Richard Friebe, Time magazine, Monday, Sep. 17, 2007,
* [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17302740&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus Energy Metabolism in Tumor Cells] , Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E., Instituto Nacional de Cardiología, Departamento de Bioquímica, Juan Badiano no. 1, Tlalpan, México DF 14080, Mexico. rafael.moreno@cardiologia.org.mx , FEBS J. 2007 Mar;274(6):1393-418.
* [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=AbstractPlus&list_uids=17404823 The cancer cell's "power plants" as promising therapeutic targets: an overview.]
* [http://www.nature.com/bjc/journal/v87/n7/abs/6600547a.html Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death] R L Aft, F W Zhang, and D Gius, British Journal of Cancer (2002) 87, 805-812. doi:10.1038/sj.bjc.6600547
* [http://www.freepatentsonline.com/6670330.html Cancer chemotherapy with 2-deoxy-D-glucose] patent
* [http://www.time.com/time/health/article/0,8599,1671684,00.html Can Ancient Herbs Treat Cancer?] Time magazine, October 15, 2007 (describes the drug trial of BZL101, a compound from the Scutellaria Barbata herb that prevents cancerous cells from undergoing glycolisis).
* [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=16033770&dopt=AbstractPlus Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis.] Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Spain; December 2005

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