Warburg hypothesis
Warburg's hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg in 1924.[1] 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.[2][3] 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."[4]
In recent years, Warburg's hypothesis has re-gained attention due to several discoveries linking impairedmitochondrial 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.[5]
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.[6] 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.[7][8]
[edit]See also
- Carcinogen
- 2-Deoxy-D-glucose
- Ketogenic diet
- Pyruvic acid
- Respiration
[edit]References
- ^ O. Warburg, K. Posener, E. Negelein: Ueber den Stoffwechsel der Tumoren; Biochemische Zeitschrift, Vol. 152, pp. 319-344, 1924. (German). Reprinted in English in the book On metabolism of tumors by O. Warburg, Publisher: Constable, London, 1930.
- ^ Bertram JS (2000). "The molecular biology of cancer". Mol. Aspects Med. 21 (6): 167–223. doi:. PMID 11173079.
- ^ Grandér D (1998). "How do mutated oncogenes and tumor suppressor genes cause cancer?". Med. Oncol. 15 (1): 20–6.doi:. PMID 9643526.
- ^ Otto Heinrich Warburg (June 30, 1966). The Prime Cause and Prevention of Cancer.
- ^ Schulz TJ, Thierbach R, Voigt A, Drewes G, Mietzner B, Steinberg P, Pfeiffer AF, Ristow M. (January 13, 2006). "Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited.". Journal of Biological Chemistry 281 (2): 977–981. doi:. PMID 16263703.
- ^ 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 (2007). "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth". Cancer Cell 11 (1): 37–51.doi:. PMID 17222789.
- ^ Jerry Adler (23 January 2007). "A New Way to Fight Cancer?". Newsweek.
- ^ Pedersen, Peter L (2007-02). "The cancer cell's "power plants" as promising therapeutic targets: an overview". Journal of bioenergetics and biomembranes 39 (1): 1–12. ISSN 0145479.
[edit]Further reading
- Warburg O (24 February 1956). "On the Origin of Cancer Cells". Science 123 (3191): 309–14.doi:. PMID 13298683.
- Ristow M (July 2006). "Oxidative metabolism in cancer growth". Curr Opin Clin Nutr Metab Care. 9 (4): 339–45. doi:. PMID 16778561.
- John Hopkins Medicine (14 October 2004). "Energy Blocker" kills Big Tumors in Rats. Press release.
- Gatenby RA, Gillies RJ (2004). "Why do cancers have high aerobic glycolysis?" (reprint). Nat Rev Cancer 4 (11): 891–9. doi:.
- Pelicano H, Martin DS, Xu RH, Huang P (2006). "Glycolysis inhibition for anticancer treatment". Oncogene25 (34): 4633–46. doi:.
- Weinhouse S (1976). "The Warburg hypothesis fifty years later". Journal of Cancer Research and Clinical Oncology 87 (2): 115–26. doi:.
- Garber K (2004). "Energy Boost: The Warburg Effect Returns in a New Theory of Cancer". Journal of the National Cancer Institute 96 (24): 1805–6. doi:. PMID 15601632.
- Seyfried TN, Mukherjee P (Oct 2005). "Targeting energy metabolism in brain cancer: review and hypothesis". Nutr Metab (Lond) 2: 30. doi:. PMID 16242042. PMC:1276814.
- Pedersen PL (Jun 2007). "Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen". J Bioenerg Biomembr. 39 (3): 211–22. doi:. PMID 17879147.
- Glycolytic enzyme inhibitors as novel anti-cancer drugs (3-bromopyruvate (3BP) and iodoacetate (IAA)), James C.K. Lai et al., Idaho State, June 2007
- Can a High-Fat Diet Beat Cancer? by Richard Friebe, Time magazine, Monday, Sep. 17, 2007,
- Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E (Mar 2007). "Energy metabolism in tumor cells". Febs J. 274 (6): 1393–418. doi:. PMID 17302740.
- Pedersen PL (Feb 2007). "The cancer cell's "power plants" as promising therapeutic targets: an overview". J Bioenerg Biomembr. 39 (1): 1–12. doi:. PMID 17404823.
- Aft RL, Zhang FW, Gius D (Sep 2002). "Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death". Br J Cancer 87 (7): 805–12. doi:. PMID 12232767.
- US patent 6670330 Cancer chemotherapy with 2-deoxy-D-glucose
- 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 glycolysis).
- Isidoro A, Casado E, Redondo A, et al. (Dec 2005). "Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis". Carcinogenesis 26 (12): 2095–104.doi:. PMID 16033770.
