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The observation that cancer cells are predominately anaerobic respirators was first made by the German biochemist Otto Heinrich Warburg in 1924 [1]. Warburg's inference that the increased rate of cytosolic fermentation in cancer cells was the result of impaired mitochondrial function has been demonstrated as correct by nearly a century of subsequent research [2]. Specific metabolic alterations observed in cancer cells include reduced pyruvic acid oxidation and increased lactic acid production[3] in the cytosol. At the core of these alterations lies perhaps the finding that cancer cells demonstrate markedly decreased activities of key respiratory proteins central to the mitochondrial electron transport chain.
Tumor pH
The extracellular micro-environment of tumors has been demonstrated to be lower in pH than healthy cells[3]The acidity of tumors can be attributed to the production of lactic acid during fermentation. Protons from reduced species such as NADH are stored in the mitochondrial inner-membrane space in healthy cells, but in cancer cells with damaged mitochondria, the NADH produced during glycolysis is oxidized in the cytoplasm, reducing pyruvate to lactate and releasing protons, lowering the cells pH. Fermenting cancer cells will also produce a greater ratio of CO2 (a lewis acid) to ATP generated.
Cytochrome C
Cytochrome C is a protein of the electron transport chain, located within the mitochondrial inner membrane. Mitochondria play a key role in initiating apoptosis, and cytochrome c appears to be a key protein in the "redox signaling" which initiates apoptosis. Damage to cytochrome c or other ETC proteins may therefore hinder the cancer cell's ability to apoptose once the cascade of uncontrolled growth and division begins.
Mitocondrial DNA (mtDNA)
Respiratory Pathways as Targets of Next Generation Cancer Drugs
References edit
- ^ Warburg, O.H. On the origin of cancer cells. Science, 1956. 123, p. 309-314
- ^ Modica-Napolitano, J.S., Singh, K.K. Mitochondrial dysfunction in cancer. Mitochondrion, 2004. 4, p. 755-762
- ^ a b Gillies, R.J., Liu, Z., Bhujwalla, Z. measurements of extracellular pH of tumors using 3-aminopropylphosphonate. American Journal of Physiology, 1994. 267, p. C195-203
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