DCA is known to be associated with toxicity and neuropathy. For example, in this study (https://www.ncbi.nlm.nih.gov/pubmed/16476929), a dose of 25 mg / kg / day of DCA caused neuropathy in all participants in the study!
Recently this article caught my attention:
Recently this article caught my attention:
High Dose Vitamin B1 Reduces Proliferation in Cancer Cell Lines Analogous to Dichloroacetate
2014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963161/
"Inhibition of PDKs by dichloracetate (DCA) exhibits a growth suppressive effect in many cancers. Recently it has been shown that the thiamine co-enzyme, thiamine pyrophosphate reduces PDK mediated phosphorylation of PDH. Therefore, the objective of this study was to determine if high dose thiamine supplementation reduces cell proliferation through a DCA like mechanism.
Results: Thiamine exhibited a lower IC50 value in both cell lines compared to DCA. Both thiamine and DCA reduced the extent of PDH phosphorylation, reduced glucose consumption, lactate production, and mitochondrial membrane potential.
...Although our findings demonstrate that doses of thiamine (mM) required to reduce cancer cell proliferation are similar to DCA, thiamine has few dose limiting toxicities."
...Although our findings demonstrate that doses of thiamine (mM) required to reduce cancer cell proliferation are similar to DCA, thiamine has few dose limiting toxicities."
According to the authors, the proliferation of cancer cells decreased by 50% at thiamine levels of 4.9 and 5.4 mM. While DCA was required 10.3 and 23.8mM. The question is, is it possible to reach a thiamine level of 4.9-5.4 mM in glioblastoma cells in the brain?
"Thiamine reduces cancer cells proliferation.
The IC50 values for DCA were 23.8 for SK-N-BE and 10.3 mM Panc-1. Comparatively, the IC50 of thiamine was lower than DCA for both cell lines with values of 4.9 for SK-N-BE and 5.4 mM for Panc-1."
The effects of Thiamine on PDH phosphorylation, glucose consumption and lactate production, mitochondrial polarization, ROS production, caspase-3 activity were estimated at 25 mM and therefore are probably not easily achievable.
I also found some studies that sulbutiamine penetrates the brain better than benfotiamine and thiamine. It also seems that sulbutiamine is safe in large doses.
"Sulbutiamine shows promising results in reducing fatigue in patients with multiple sclerosis. Sulbutiamine is a lipophilic compound that crosses the blood-brain barrier more readily than thiamine and increases the levels of thiamine and thiamine phosphate esters in the brain."
2008 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435522/
"...We previously found that sulbutiamine treatment significantly increases thiamine, ThMP, ThDP and ThTP content of rat brain, while the present results show that benfotiamine, at a twice higher dose, is unable to raise the levels of intracerebral thiamine phosphate derivatives.
...Furthermore our results on cultured neuroblastoma cells show that benfotiamine, in contrast to sulbutiamine, does not easily cross cell membranes.
...Our results show that oral administration of benfotiamine leads to significant increases in thiamine, ThMP and ThDP levels in blood, liver but not in the brain. This difference is in agreement with the known pharmacological profile of benfotiamine, i.e. the beneficial effects of the drug concern peripheral tissues but not the central nervous system."
1999 https://www.ncbi.nlm.nih.gov/pubmed/12973384
"Sulbutiamine, a highly lipophilic thiamine derivative, is the only antiasthenic compound known to cross the blood-brain barrier and to be selectively active on specific brain structures directly involved in asthenia."
1999 https://www.ncbi.nlm.nih.gov/pubmed/12973384
"Sulbutiamine, a highly lipophilic thiamine derivative, is the only antiasthenic compound known to cross the blood-brain barrier and to be selectively active on specific brain structures directly involved in asthenia."
Sulbutiamine is available as a dietary supplement. Unfortunately, there is not enough information about the risk of its effect on tumor growth at low and medium doses and what should be the high dose for an effect similar to DCA.
Thanks for researching this in such detail. The one red flag in all this is the extremely high concentrations required in the lab to inhibit cancer cell proliferation. There are extremely few drugs that can reach millimolar (mM) concentrations in the blood plasma, let alone the central nervous system. After a single high dose (1500 mg) of thiamine hydrochloride, peak plasma concentrations of thiamine are 397 nanomolar. That is 0.397 micromolar, or 0.000397 millimolar. I can do a bit more research on pharmacokinetics of sulbutiamine today, but I highly doubt that its improved bioavailability will lead to plasma concentrations anywhere close to 1 mM.
ReplyDeleteThis is the reason I look for at least rodent evidence and pay relatively little attention to in vitro studies, where there is no limit to the drug concentrations scientists can use. At least with animals, you have to show that the drug can be effective without killing the animals with toxic side effects.
High micromolar concentrations of DCA are achievable in humans, still not quite millimolar, but a lot closer to it than most drugs.
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