Sutendra, G., and E. Michelakis. “Pyruvate dehydrogenase kinase as a novel theraputic target in oncology.” Frontiers in Oncology, March 2013.
So i found this concise article that taught me a lot about cancer that i didn’t know and it’s stuff that i can now understand because of BioChem and what we covered on glycolysis, TCA and TEC!!
Cancer is most commonly detected by positron-emmision tomography (PET) scanning, this detects the uptake of glucose by cells because it was discovered that cancer cells have a much higher uptake of glucose than non cancer cells. But why?
Well cancer cells have a different metabolism than normal cells, instead of using both glycolysis and mitochondrion glucose oxidation (GO) cancer cells switch to relying on glycolysis only… at first this was thought to be a result of conditions created as a result of them being cancer cells e.g. hypoxia (which is a lack of oxygen in cells and tissues) but recent studies showed that these conditions occurred in cells not under hypoxic conditions and this change in metabolism was shown to be a mechanism for the cancer development rather than a symptom of the cancer.
So now using this knowledge investigations were done to understand why cancer cells adopt this alternative metabolic phenotype and how this information could be used to selectively treat cancer.
This switch may be caused by the activation of HIF which is a transcription factor that regulates many of the enzymes in glycolysis, the key one for the study being pyruvate dehydrogenase kinase (PDK) as it is activated in several different types of cancers, PDK inhibits the pyruvate dehydrogenase (PDH) enzyme complex , which we know is responsible for the link reaction and converting pyruvate into AcetylCoA so that it can enter the mitochondria, because PDK inhibits PDH it also prevents the cell from using glycolysis along side mitochondrion GO and instead makes it rely solely on glycolysis.
Cancer cells are generally resistant to apoptosis ( cell death) because of this metabolic switch. Proper functioning mitochondria are what regulate the pathway that triggers apoptosis, by relying solely on glycolysis, mitochondria begin to function improperly and apoptosis is suppressed in cancer cells. In the glycosidic environment within the cell changes to the membrane protein of the mitochondria occur on one such channel allows for negatively charged ions to leave, due to the changes that occur these anions can no longer leave and long story short the membrane potential of the mitochondrial membrane is altered in such a way that inhibits apoptisis, this is what allows cancer cells to proliferate at such a high rate.
Ok so now we have an idea of how cancer cells do their do now we can begin to think about how we can reverse this process so that the cell will return to a normal metabolism allowing apoptosis to occur.
For this to happen we would have to find a way to allow pyruvate to once again enter the mitochondria and allow glucose oxidation to occur this in turn will mean that the membrane potential will return to normal thresholds and as a result the mechanism to trigger apoptosis will be functional which is what the molecule dichloroacetate (DCA) does :D
It activates PDH and thus allows for pyruvate to once again enter the mitochondria and as a result GO is able to occur in conjunction with glycolysis i keep stressing this because it can’t be one or the other it has to be both glycolysis and GO in the mitochondria occurring side by side to ensure that the apoptosis mechanism is functional…
DCA is super awesome, cause it works on cancer cells and has no effect on non- cancer cells, thus it is selective which is a big deal because most cancer treatments aren’t selective and the ones that are don’t work all that efficiently so this is a big step forward for cancer treatments.
Both in vitro and in vivo trials were conducted using DCA and results showed and improvement in patients and a decrease in the proliferation of tumours *thumbs up for science*
Trials showed that post-DCA treatment tissues had decreased expression of factors such as HIF1a leading to decreases in tumour size and vascularity illustrated in the two images below :
Trials also found through treatment with DCA that other metabolic pathways could be used to target cancer cells e.g. boxidation of fatty acid pathway which this pathway is inhibited it naturally triggers the promotion and expression of PDH which increases GO levels in the mitochondria ….
A lot of research is still being done but steps are being made to fight cancer and no just small steps big ones to J
As always thanks for reading ;)