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Case Studies
Glycolysis and cancer
The majority of cancer cells are resistant in apoptosis and researchers then asked whether this resistance is related to particular
properties of the mitochondria in cancer cells which are distinct from normal, healthy cells (Gogvadze et al. 2008).
It was first suggested by Otto Warbrug in 1926 that a decrease in mitochondrial energy metabolism may lead to developing
cancer. Warburg also found that cancer cells produce the majority of their ATP through glycolysis in aerobic conditions,
and it is now known that they also have high glycolysis rates in anaerobic conditions and that there is a correlation between
glycolytic production and the aggressiveness of the cancer cell (Gogvadze et al. 2008).
This increase in glycolysis is due to the fast proliferation which is characteristic of cancer cells. As they proliferate
at such a fast rate, the conditions become hypoxic as there is not an adequate supply of oxygen. Under hypoxic conditions
mitochondria cannot produce enough ATP to sustain the cell, so the glycolytic pathway becomes up-regulated by the induction
of HIF1α which stimulates key parts of the pathway. Hexokinase is also maintained by Akt. When the ATP production
in the cell shifts to glycolysis, mitochondrial activity slows down, the mitochondria consume less oxygen and less ATP is
produced. This enhanced dependence on glycolysis supports the proliferation of the cancer, and the high intracellular glucose
concentration allows the cells to redirect the excess pyruvate produced to lipid synthesis which is necessary for assembling
the membrane (Gogvadze et al. 2008).
Inhibiting the glycolysis pathway is thought to severely deplete the ATP, particularly in hypoxic conditions and so cause
cell death through starvation. It is often used in conjunction with other therapies, as simply inhibiting the pathway often
has not been potent enough to kill the cancer through starvation. There are many glycolysis inhibitors that are being investigated
and several are going through trials at the moment to establish their effectiveness. The theory behind this combination is
that healthy cells get their energy for growth mainly from respiration, and a small amount from glycolysis, whereas cancer
cells are dependent on glycolysis for their energy. This creates a natural target and cancer cells can be made to starve
by inhibiting glycolysis, while healthy cells are not affected (Gogvadze et al. 2008, Gatenby and Gillies, 2007).
The most obvious target for inhibitors is hexokinase, the first enzyme in the glycolysis pathway, and some have been tested
and had anti-tumour effects like 3-Bromopyruvate (Gatenby and Gillie, 2007). Another drug which has also been tested is one
associated with 3-Bromopyruvate called 3-Bromo-2-oxopropionate-1-propylester or 3-BrOP has also been tested. 3-BrOP works
by being converted to 3-Bromopyruvate upon entry to the cell, where it can then inhibit hexokinase. 3-BrOP has also been
trialled with an mTOR inhibitor rapamycin which combined shut down the energy source and hastened cell death in cancer cells
(Farris, 2008). This combined method was found to be 90% effective in acute lymphocytic leukaemia tissue cultures.
Other parts of the pathway which are commonly inhibited are the pyruvate dehydrogenase complex and ATP citrate lyase (Bucay,
2007).
Another way the glycolytic pathway can be inhibited is by citrate. Citrate inhibits phosphofructokinase, pyruvate dehydrogenase
complex and succinate dehydrogenase (Krebs cycle), and is able to be taken orally. It is at the moment going through trials
(Bucay, 2007).
Analogues such as 2DG are also used to block the glycolysis pathway by competing with glucose to enter the pathway. Then
once phosphorylated by hexokinase it can no longer be metabolised, and so cause metabolism to slow down (Gatenby and Gillies,
2007).
Another glycolysis inhibitor, BZL101, is also being researched in treating cancer working on the same principle that healthy
cells do not depend on glycolysis to make energy, but cancer cells do. In this case the drug has been trialled with breast
cancer cells. BZL101 is an aqueous extract from Scutellaria barbata and has several active ingredients which combined cause
cancerous cells to undergo apoptosis, but not healthy cells (Bionovo Inc, 2008).
Sources:
http://finance.abc7chicago.com/abc?Account=wls&GUID-5054779&Page=MediaViewer&Ticker=BNV1
http://www.eurekalert.org/pub_releases/2008-05/uotm-ndc051508.php
Gogvadze. V., Orrenius. S., Zhivotovsky. B. (2008) Mitochondria in cancer cells: What is so special about them? Trends
in Cell Biology 18, 166-173.
DeBerardinis. R.S., Lum. J.J., Hatzivassiliou. G., Thompson. C.B. (2008) The biology of cancer: Metabolic reprogramming
fuels cell growth and proliferation. Cell Metabolism 7, 11-20.
Gatenby. R.A., Gillies. R.J. (2007) Glycolysis in cancer: A potential target for therapy. The International Journal of
Biochemistry and Cell Biology 39, 1358-1366.
Bucay. A.H (2007) The biological significance of cancer: Mitochondria as the source of cancer and the inhibition of glycolysis
with citrate as a cancer treatment. Medical Hypotheses 69, 826-828.
Pedersen. P.L. (2007) The cancer cell’s “power plants” as promising therapeutic targets:
An overview. J Bioenerg Biomembr 39, 1-12.
Rugo. H., Shtivelman. E., Perez. A., Vogel. C., Franco. S., Tan Chiu. E., Melisko. M., Tagliaferri. M., Cohen. I., Shoemaker.
M., Tran. Z., Tripathy. D (2007) Phase I trial and antitumour effects of BZL101 for patients with advanced breast cancer.
Breast Cancer Res Treat 105, 17-28.
Glycolysis and epilepsy
Diabetes drug may hold potential as treatment for epilepsy, using the same mechanism as ketogenic diet (news-medical.net,
2008).
Two years ago at the University of Winconsin-Madison researchers were able to suppress epileptic seizures in rats by giving
them a glycolytic inhibitor, so inhibiting the brain’s ability to turn sugar into excess energy and blocking expression
of seizure related genes (news-medical.net, 2008).
Epileptics often follow a strict diet called a ketogenic diet which is high in fat and protein, and free of starch and
sugar. This causes ketone bodies to increase in the person following the diet, and also causes their oxidation in the brain
to rise. When this happens their oxidation in the brain rises too and they are used as protective molecules in refractive
epilepsy (Haces et al, 2008). Epileptic seizures can cause permanent brain damage, but ketone bodies and pyruvate are able
to help protect the brain from this damage (Kim et al, 2007). During convulsive seizures large metabolic demands are put
onto the central nervous system and this is met primarily by glucose consumption which is the main source of energy for the
brain (Darbin et al, 2005). This, it is reasoned will affect glycolysis. Researchers looked at to how to tap into the glycolysis
pathway without having to use the diet and came up with a molecule called 2-Deoxy-Dglucose (2-DG). This molecule tricks the
body into thinking it is sugar and so the cells stop using the real thing as an energy source. 2DG competes with glucose
to enter the pathway. However once it has been phosphorylated by hexokinase then it can no longer be metabolised, and so
cause glycolysis to slow down (Hitti, 2006).
The researchers also looked at the sensors which detect the amount of blood glucose and hit upon the idea that Metfornine,
a drug licensed for use in diabetes treatment, also controls blood sugar levels as the drug switches on the sensor (news-medical.net,
2008).
Sources:
http://www.news-medical.net/?id=37144
http://www.webmd.com/epilepsy/news/20061016/diet-may-inspire-new-epilepsy-drugs
http://www.epilepsyresearch.org.uk/news/arch/2006/D611sugar.htm
Haces. M.L., Hernandez-Fonseca. K., Medina-Campos. O.N., Montiel. T., Pedroza-Chavern. J., Massieu. L. (2008) Antioxidant
capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycaemic conditions. Experimental
Neurology 211, 85-96.
Kim. T-Y., Yi. J-S., Chung. S-J., Kim. D-K., Byun. H-R., Lee. J-Y., Koh. J-Y. (2007) Pyruvate protects against kainate
induced epileptic brain damage in rats. Experimental Neurology 208, 159-167.
Darbin. O., Risso. J.J., Carre. E., Lonjon. M., Naritoku. D.K. (2005) Metabolic changes in rat striatum following convulsive
seizures. Brain Research 1050, 124-129.
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