Studies Of Caloric Restriction, Resveratrol And Sirt1 Demonstrate A ?Metabotype’ Continuum From Cellular Rejuvenation To Aging To Cancer
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mimicking glycolytic blocking agents such as 2-deoxy glucose and 5-thio D glucose, can kill up to 99.999% of cancer cells in a few hours while leaving normal dividing cells alive, with the cancer cells being radiation sensitive and the normal cells being radiation insensitive. These agents slam glycolytic ATP production to a halt leaving only pyruvate starved mitochondrial ATP production to remain. Being glycolysis end product dependant, much more so than most normal cells, cancer cells die, while normal cells can utilize, or switch off to alternate fuels, more readily. Unfortunately, these results don’t translate to in-vivo use because the therapeutic dose is to close to the contraindicating dose, probably because they are glucose analogues. Brain cells are highly dependant upon glucose, for instance. In cancer cells, glycolysis often produces many times more pyruvate than the inefficient mitochondria can assimilate, so the excess pyruvate is converted to lactate for cell export to the liver, where it is converted to glucose for re-export to the tumor, in a closed loop system called the cori cycle. Other cells, such as hypoxic cells and low oxidative fast twitch muscle cells, can reversibly utilize the cori cycle, while cancer cells are much more entrenched in the cori loop. Hyperacidification by lactic acid export blockers has instituted differential cancer cell kill, in many cases, but usually fails to finally eradicate tumors that adapt to hypoxic conditions. Also, it is necessary, as with glucose feedstock blocking, to thread a narrow path between efficacy and contraindication. Bypassing cell glucose importation and lactate export systems may efficaciously demonstrate an alternative outcome. A recent strategy, applied across a broad spectrum of tumors in mice, utilizes dichloroacetate (DCA) to block a fetal puruvate kinase (FPK) enzyme in these tumors, thus renormalizing metabolic flow away from anabolism, and stopping cell growth. Apparently the switchout from adult PK to FPK is very common in such mouse tumors. Unfortunately, the results are so promising, and dichloroacetate, being a common unpatentable reagent, have led to a growing illegal market for dichloroacetate, among desperate cancer victims. Caloric restriction and antioxidants both have impact on cancer incidence and severity. Carcinogenesis is both delayed, and once initiated, growth rates are slowed. It would be very interesting to see the results of resveratrol and dichloroacetate together. One could postulate a synergistic effect, in which dichloroacetate renormalizes glycolytic flow, and resveratrol reinforces the effect via anti-oxidation and/or mitochondrial biogenesis. Then again, things may not be so simple. The FPK system might not work the same way in humans as it does in mice, because people using DCA are reporting huge cell kill rates in their tumors and the associated dead cell load problems, indicating that DCA is acting more as a blocking agent than a pathway switching agent. If true, it could all be for the better, as kill is far more preferred than renormalization, as it allows the therapy to be stopped, at some point, instead of having to remain interminable. Besides, long term use of DCA is hepatotoxic.
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