ATP citrate lyase is an important enzyme for he fast dividing cancer cells
ATP citrate lyase (ACL or ACLY) is an intracellular enzyme (located in cytosol) responsible for the conversion of citrate that comes out of the mitochondria, to acetyl-CoA and oxaloacetate.
ATP citrate lyase is primarily expressed in lipogenic tissues. Other vegetative tissues express little to no levels of the enzyme. However, it has been it discovered that the fast growing cancer cells are characterized by a high level of ATP citrate lyase activity. (Ref.)
Some are even suggesting that high level of acetyl-CoA required for cellular growth is what activates glycolysis and increased mitochondrial production of citrate, and the activity of ATP citrate lyase.
Indeed, in cancer cells the energy supply is produced mainly by the glycolysis of glucose, and part of the glycolytically derived pyruvate enters the truncated tricarboxylic acid cycle (TCA cycle, also known as citric acid cycle) in the mitochondria, where citrate is exported to cytosol via the tricarboxylate transporter. In the cytosol, ACLY enzyme coverts citrate in acetyl-CoA (and oxaloacetate) which is very much needed by the fast growing cells to e.g. maintain an active chromatin structure through histone acetylation, and to produce specialized lipids much needed for various intracellular processes. In other words, ACLY is the enzyme that links glycolysis to fatty acid/lipid synthesis.
If acetyl-CoA is important for the cancer cells and if ACLY is the enzyme that converts acetyl-CoA, one expected effect is that if we inhibit ACLY, there will be a build-up of citrate in the cytosol , which in turn will lead to:
1. a reduction of acetyl-CoA available of the fast growing cancer cells
2. a build-up of citrate in cytosol that can act as a negative regulator of the glycolytic pathway, i.e. suppressing the consumption of glucose and thus the energy production. This is because Citrate down regulates glycolisis since it is an inhibitor of phosphofructokinase (PFK), the 2nd key enzyme of glycolysis pathway (Ref.).
ATP citrate lyase inhibitors: Hydroxycitrate (HCA) one of the most accessible inhibitors
Indeed, here is a patent that proposed ACLY inhibition as a method for killing cancer, specifically the highly glycolitic ones http://www.google.com/patents/EP2633856A2?cl=en
And here is an article discussing ACLY (or ACL which is the same) inhibitors (Ref)
One of the most known inhibitors of ACLY is Hydroxycitrate (HCA) which is derived from fruit rinds of Garcinia species including Garcinia cambogia, Garcinia indica. HCA is a widely available supplement, e.g. http://www.iherb.com/search?kw=hca#p=1 Currently HCA is used as a supplement for weight loss.
Another ACLY inhibitor is Bempedoic acid (ETC-1002), currently (2017) in clinical trials investigated as a potential drug to reduce reduced LDL-C in patients who cannot tolarate statins (Ref.). The drug is investigated by Esperion Therapeutics Inc., a late-stage pharmaceutical company.
ACLY inhibition with HCA: Promising results in Human
One of the first group of doctors and scientist applying this concept in humans is prof Laurent Schwartz and coleagues in France (Association Cancer & Metabolisme). Following the screening of various drugs they came up with HCA & Alpha Lipoic Acid (ALA) as one of the best combinations to kill cancer and patented this (Ref.) under the name METABLOC.
I think this combination of HCA and ALA makes sense since ALA will redirect pyruvate towards the mitochondria (in a way similar to Dichloroacetate (DCA) – the mechanism will be discussed another time) which will finally go out of mitochondria as citrate and HCA will inhibit the conversion of citrate to acetyl-CoA that will lead to the accumulation of citrate in cytosol and down regulation of glycolisis. (An idea: on this line, it may be good to add citrate as a suppliment next to HCA and ALA to possibly increase the cellular citrate?). Citrate down regulates glycolisis since citrate is an inhibitor of phosphofructokinase (PFK), the 2nd key enzyme of glycolysis pathway (Ref.).
Bellow are some of the published articles after applying this concept on humans.
Administration and Side effects
Dose: In most of the clinical trials they used HCA (The minimum dose of HCA was 1.2 g/day and the maximum dose was 3 g/day) in combination with Alpha Lipoic Acid (The minimum oral dose of α-LA administered was 0.4 g/day, and the maximum dose was 1.8 g/day.) Example of HCA source is Super CitriMax
Side effects: Some patients had side effects such as stomach pain which disappeared on using proton pump inhibitors or by reducing the dose. According to various publications HCA is safe in humans at 5g/day with no specific toxicity. (Ref) The dose seems to be safe in humans up to 13.5g/day (Ref)
Ideas to improve the treatment protocol:
One ideas is to add Citrate supplements due to the reasons discussed above.
Another idea is to add DCA (Dichloroacetate) since DCA acts in a similar way as ALA while it may be more effective in reaching the cell.
Both Citrate and DCA are know as having anti cancer effects alone.
Yet another idea discussed in the patent (Ref.) is to use a tricarboxylate transporter inhibitor (such as Oxaloacetate). The tricarboxylate transporter is responsible for exporting citrate from the mitochondria down the concentration gradient to the cytosol. It’s inhibition would lead to accumulation of citrate into the mitochondria.
Update: 10-April-2017: when ACLYL is inhibited by HCA, tumor cells will express ACSS2 enzyme to convert acetate into the actyl-CoA (Ref.). ACSS2 level is modulated by SREBP2 (Ref.) and SREBP2 in turn can be modulated by Vitamin E derivatives (tocotrienols) (Ref.)
- Dose: not yet sure what would be the best dose
- Source: Online available supplements such as this one.
Note: Thank you to Frank Liu for heads up on this point via his comment.
In the clinical trials using HCA some people saw tumor reduction and after some time it cam back. In that case, the escape mechanism may be explained by the following https://www.cancertreatmentsresearch.com/?p=913. If that is the case, addition of ACSS2 inhibitor will solve the issue. I already passed over this idea to the relevant scientists and doctors in the field. 😉
With the above in mind, and given its safety profile, accessibility and low cost, I would add HCA to any anti cancer treatment protocol.
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