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.
New Cancer Paradigm and New Treatment: The Example of METABLOC
Metabolic cancer treatment: Intermediate results of a clinical study
The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous α-Lipoic Acid/Low-Dose Naltrexone Protocol
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.
This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.
37 thoughts on “Another weak spot of cancer cells: ATP citrate lyase inhibition”
Really you are amazing.Where did you find those lots of valuable,cheap,effective combinations?You worked too much as i see.
I like the the article that you linked(In every article we see the importance of combinations).
We began HCA(1000mgxday, but %50 HCA written on box?) yesterday near DCA+others+chemo.
But i am not sure about adding citric acid to our protocol.As we talked before DCA also may rise the citric acid accumulation.
I wonder that if more citric acid more benefit?,but with higher HCA?( What should be the dosage of HCA after adding DCA+citric acid)?
A hard question to answer i know,may be we have to wait for the results before adding citric acid.
We have only 2 months before surgery.
Thank you. Indeed, most of the HCA capsules contain 50% and some contain 70%.
If it is to think from the mechanism point of view, the more accumulated citric acid in the cancer cells the higher the chance to inhibit glycolisis. The HCA dose is described in the article cited above. I would expect that the citric acid accumulation doesn’t have impact on the HCA mechanism. So from that point of view, I would not increase the dose of HCA higher than that range suggested in the article as effective. According to the experience shared in the article some patients may experience side effects from higher doses of HCA that may be eliminated when using proton pump inhibitors such as Omeprazole.
Thank you very much Daniel.This helps me too much.
Post molto Interessante e trovo corretto tutte le informazioni….
Cè però un problema!
Se il citrato che si accumula nel citoplasma va a bloccare la PFK (fosfofruttochinasi), la via del glucosio viene dirottata verso laa via dei pentosio fosfato che è un altra via molto attiva nel cancro.
Ora mi chiedo: usare inibitori della Citrato Liasi non si rischia di favorire la via dei pentosio Fosfato?
Un Saluto dall’Italia (TARANTO)
“Post Very Interesting and I find all information correct ….
But there is a problem!
If citrate accumulates in the cytoplasm to block PFK (phosphofructoquinase), the pathway of glucose is diverted to the pathway of pentose phosphate which is another very active pathway in cancer.
Now I wonder: using Lira Citrate inhibitors does not risk fostering the pathway of Phosphate pentose?
Thank you Daniel
A Greeting from Italy (TARANTO)”
Ciao Liborio and thank you for your comment. Indeed pentose phosphate pathway (PPP) is very relevant in cancer and inhibition of glyco may redirect glucose and in turn fuel PPP. And as explained here “PPP is especially critical for cancer cells because it generates not only pentose phosphates to supply their high rate of nucleic acid synthesis, but also provides NADPH, which is required for both the synthesis of fatty acids and cell survival under stress conditions.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329227/
Therefore, if we inhibit glycolisis after G6P (see https://www.cancertreatmentsresearch.com/acetate-fuels-cancer/) we also need to make sure we inhibit or reduce PPP or alternatively the activity of mithocondria which otherwise will switch on fatty acids.
Interestingly, PPP can be reduced/inhibited by DHEA, which seems to inhibit glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway. DHEA can be found as a supplement online http://www.webmd.com/diet/dhea-supplements#1
BUT, we need to be careful because as the reference above states, “in contrast to the expected resistance exerted by the elevated PPP in response to certain drugs, the PPP may sensitize cells to other therapeutic drugs. Indeed, it appears that the high levels of NADPH generated by a hyperactive PPP sensitize cells to anthracyclines. Anthracyclines are a class of antibiotics used in cancer therapy, and the most commonly used member of this class is adriamycin, also known as doxorubicin. Anthracyclines are metabolized by cytochrome p450 reductase to produce free radicals, which induce cytotoxicity72. Because NADPH is a cofactor that is required for this activity of cytochrome p450, the high levels of NADPH generated by the PPP may sensitize cancer cells to doxorubicin”.
– CA may lead to increased activity of PPP
– PPP is relevant in cancer and its inhibition may help fighting cancer
– PPP may be inhibited by DHEA, which can be found as a supplement online
– some tumors (such as adrenocortical carcinoma) naturally produce high levels of intracellular DHEA, inhibiting PPP
– but active PPP may help some specific chemos such as doxorubicin – therefore CA during doxorubicin may be beneficial
I hope this addresses your question.
Forse la G6PD è possibile inibirla con farmaci per la malaria, come la clorichina e l’artemisia?
Btw, I just clicked on your name and saw your very nice website http://liborioquinto.altervista.org/
Nice to see that 🙂
sono Lusingato; buona Giornata
Tecnologo Alimentare Dottor Liborio Quinto
I’ve researched the role of glutamine a little bit and found that glutamine can be the result of MYC, or the result of autophagy of cells. The glutamine is then converted to glutamate by Glutaminase, and further converted into a-Ketogluterate and pushed into the Krebs cycle by aminotransferase or GLUD1 where it can be used to generate ATP.
This image explains the process, and I’m sure you understand it already.
My thought is that maybe combining Chloroquine (which is illustrated to block the autophagy pathway in the image), along with DCA/Metformin to disrupt glucose metabolism along with intra-mitochondrial processes, plus HCA to block the acetate pathway, plus a Glutaminase, aminotransferase, or GLUD1 inhibitor (since MYC itself is difficult to inhibit) would be a strategy to try out.
Or chloroquine may be rendered unnecessary by inhibiting one of the later processes like TA/GLUD1 or Glutaminase.
Hi Meech, all the elements you have mentioned are standing out in terms of anti cancer potential. Same with Chloroquine. Based on a statistic I made some time ago from RGCC data, I’ve seen that Chloroquine has good potential against cancer cells from most patients. So, I would always consider at least some cycles with Chloroquine.
The strategy sounds good to me. I would just add that it may be good if you address some pathways with multiple elements since their availability at the tumor location may depend on so many aspects and can be different from patient to patient as well as depending on the tumor location.
Thank you for sharing your idea.
They said 2 drugs(HCA+ALA)is not enough and only slows the tumor growth,so you have to put 3th drug near them to shrink tumors.
And they works for limited time and i am always thinking about it.
My idea is like this:If we want a cure,we have to fight with everything,because they all works for limited time.
Half knowledge is the most dangerous thing in cancer treatment,like what i am trying to do at this time.
Yes i belive metabolic treatment of cancer BUT when my mother was diagnosed with peritoneal ovca,we never used curcumin,quercetin,artemisinin.metformin,2DG,ketogenic diet,HBOT,melatonin,DCA,statins,MG,TM,or any angiogenesis inhibitor, OR etc…and etc..
Her CA125 declined to 5 from 400 in 3 months.If chemo works,it really works.I am thinking if we tried those vaulable drugs when she was diagnosed,may be complete responce.But now our all DNA changed because of chemo.
I have been in Daniels website for about 2-3 months.I am trying to do with all my best as you see but i feel it is not enough.
Sometimes i find myself reading,but not understanding.
Our friends are talking about high fever with toxins or oleander etc.,i wrote lots of times that high fever is not enough to kill cancer on patients heavily prethreated with chemo.And you can not catch highfever everytime after chemo.This is my experience with lots of patients.You lost lots of valuable cells while on chemo which are working for immunity.Mechanism is very clear.
If i know more ,i will exactly share it with others,like you Meech.
And i have suspicious about my mothers diagnosis.My grandmother passed away because of lung mesothelioma.
Whole family took aspesdos 50 years before.And my mother was there.When i look her biopsy reports there are some interesting findings.It looks like peritoneal mesothelioma,but they said ovary of peritoneal cancer..And there are some necrotic places on lung came from past tuberculosis.
Past tuberculosis can cause peritoneal cancer or peritoneal tuberculosis aswell.Or cancer patients are highly danger on tuberculosis.
Really i have lots of troubles.There is no primary cause they found with her disease.Only on periton metastasis.
There are bacterias and viruses they found that cause cancer.This is real,i very believe it.Nearly%20 of cancers they are thinking.
But if more of them are the results of bacteria or virus?
Why we use antibiotics like salinomycin,or tuberculos drug like Chloroquine as your idea?
We can show some molecular way of explanation but it is not enough.
Why treatment is same like ebola or other rare diseases. Alkylating agents. Warms can cause cancer also.
They all can change DNA also etc.
May be just a legend but we know some of the cancer have directly correlation with viruses or bacteria.Like HPV and helicobacter pylori .
Now we ALL are trying for chemo to work like before.
After citric acid treatment of mesothelioma cells, nearly all of them are killed however with a non cytotoxic dose of CHEMO in an experiment.But you said you saw no or less benefit with citric acid.I am always thinking of your words.
I just want to tell what is in my mind.May be my thoughts are going to change day by day.
It’s a highly frustrating disease with many escape mechanisms and many ways to avoid being killed. It’s highly adaptive and that ends up being very frustrating since like you said, treatments may only work for a period and cease to work once the cancerous cells figure out another method by which to survive.
The diagnoses are not always crystal clear as well. I know cancers where primary tumours can’t be found happen with some regularity.
Important to note that I ceased citric acid treatment after maybe two to three months due to stomach upset. For me, it’s difficult to even drink lemon juice as I suspect I have some form of citric acid intolerance. So taking 5g/day was tough to handle. I did have a lot of hope for it just because it was a cheap and simple method.
Chemotherapy is definitely something which has immediate and direct efficacy but it’s important to note that killing cancer cells is incredibly easy. What’s hard is killing cancer cells while sparing normal cells, and for a lot of people, chemotherapy has an unacceptable toxicity profile. I had a friend of mine die last year due to sepsis after pneumonia due to the chemotherapy eliminating his immune cells.
The goal for all of us is to target cancer cells without harming the rest of our bodies and that’s why this becomes a huge challenge and a big source of frustration.
Hang in there; hopefully with enough experimentation we can figure something out.
Thank you very much Meech,
You are almost right,we tried lots of things to kill cancer cells without chemo.But didnt have any success without chemo.
Now it looks like chemo also donesnt work.Citric acid+HCA is my last hope.May be it totally blocks the fuel with others.A hope.
While I also think is a challenge killing advanced cancer, in the end this is the major challenge of humanity, based on the facts shared on this website (case reports, many of which are published in respectable journals) it is also clear that is possible to kill cancer both with the help or without the help of what we today chemo. (Actually, almost all treatments are chemo just that some are toxic and others not.). What is important is, like Meech started to do, to have a look at everything we understand today about cancer and try to address as many of the resistance pathways as possible at the same time. We also have to accept that any drug or supplement we may use may come with some potential for side effects. You see, even Citric Acid. I also think that every treatment strategy should focus around a core treatment, and support that from as many angles as possible. Not just try to fit more treatments together, but try to do that in a clever way. I know this is easy to say, hard to do, but it is possible. Many of the friends and readers who are discussing lately on the website are also using Chemo. But I am constantly surprised how this opportunity is lost by not trying to access treatments that could very much support chemo. Like using Sal and/or Phlorizin https://www.cancertreatmentsresearch.com/?p=736. I never saw much discussion on Phlorizin and based on the many results described by respectable US mainstream doctor (supported by clear science as well), Phlorizin is a gemstone when it comes to supporting Chemo. Just have a look at the article. Next, I haven’t heard much about trying to inhibit multidrug resistance pumps that are over expressed in cancer and typically confers resistance to chemo as discussed here https://www.cancertreatmentsresearch.com/?p=970
My point is that all have to think deeper about what they are doing as there is so much more that it can be done!
You are very right.We use toxic chemo despite knowing not very effective after some time.
And loosing too many healthy cells.
We are loosing opportunity,time without using salinomycin,Phlorizin etc.,if we will go with chemo as you mentioned me before.
Dear ergin, i don’t think i have much to contribute with sadly.
I am deeply sad to see i am not the only one fighting but also happy i am not alone and maybe together we can succeed.
After months of research on the internet, the only thing that promisses to kill resistant cancer cells is Paw Paw capsules / Graviola.
I must say, me and my mother have tried it with a 1 month hardcore protocol. 3X2Capsules of Paw Paw and 10g Graviola Powder Tea every 4 hours.
The resulting blood tests were very encouraging at first just after begining 28.05 CEA.
The followup test for comparison gave us something above 43. after 20 days.
Could this be the result of cancer cells dying? I can’t be sure and i can’t risk it.
Still my mother is taking Paw Paw capsules and Aspirin then some ginger tea, diet and coffee enemas. We’re doing our best to at least buy time with what we have.
The long story https://www.youtube.com/watch?v=hD6MGd0Dz5o
The short story https://www.youtube.com/watch?v=ED7yax2ee4c
I wouldn’t bet anything on it, maybe someone would have something better to say about the above metioned.
I had high hopes for them being able to help my mothers situation but high dose aspirin and cbd oil did look better as we did that before them but i don’t have tests to show it.
Similarly i don’t know what to expect anymore, still confused, hurt, demoralized, still looking for answers, hope and solutions.
We didn’t do any chemo, just massive surgery.
I feel time is slipping away and experiments have to be shorter and shorter.
I am very curious about your curent complete protocol after reading your comments around.
I feel we are all in similar emotional states.
We’re going to try DCA, ALA, HCA, CA, Cimetidine, Meformin – BIG THANKS to Daniel. I wouldn’t know where to stop saying THANK YOU! For all the help and kind words.
Looking forward for your thoughts dear ergin.
Thank you Alex,i ll write you tonight
The role of fatty acid β-oxidation in lymphangiogenesis.
ATP-citrate lyase controls a glucose-to-acetate metabolic switch.
Tumor cell metabolism: cancer’s Achilles’ heel.
Cancer as a mitochondrial metabolic disease.
A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells.
Hi Daniel, about your last update After Frank Liu remark:
You have a more recent research pub with an other simpler treatment:
Apigenin attenuate SREBP-2
For dosage it is simply a spoon of fresh parsel by day !
Have you contacted dr SCHWARTZ from France ?
If yes I will contact him for correcting.
Thank you Malypaet!
I always found Apigenin one of the relevant elements in fighting cancer, and is good to see now it fits well here. How do you know a spoon of fresh parsley by day contains enough Apigenin?
I was in contact with dr. Schwartz sometime in 2014. We met each other in Paris. But I did not discussed with him lately. I only made him aware at some point about the need to address ACSS2.
Interestingly, low extracelular pH also activates SREBP-2. Here is a very recent paper on that https://www.ncbi.nlm.nih.gov/pubmed/28249167 Therefore inhibiting glycolisis or proton pump transporters it is also a way to control SREBP-2. This finding is nice since it connects cholesterol biosynthesis with pH and glycolisis. The control of pH is discussed here https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/
I also implemented this new info here https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/
The motto of Dr. SCHWARTZ:
a simple and non-toxic treatment
Parsley fits well with that 🙂
For explaining dosage:
Vitamin E dosing
Something of possible relevance with regards to hormones and HCA. https://www.ncbi.nlm.nih.gov/pubmed/27145492
I’m not certain of what that means but it may prove of value.
Thank you. Very interesting indeed. Would be interesting to know if this can happen in humans as well.
Thank you Daniel,
I hope you’re doing alright.
As for T4 levels going higher due to HCA, i’m uncertain of the speed the T4 values can change.
If they are slow changing than looking at my mother’s tests data, it would seem the research doesn’t apply to her.
Thank you again for everything.
In my experience, lipoic acid can be quite upsetting to the digestive system and also cause reflux. In addition to using a PPI, using R-lipoic acid instead of ALA can provide a more biologically active dose so that less lipoic acid has to be taken. As the wiki article below explains, ALA is made of about 50% R-lipoic acid and 50% S-lipoic acid (stereoisomers), but only the R-lipoic is found in nature and is fully biologically active. Many supplement companies sell R-lipoic acid, generally stating that R-lipoic is about twice as potent as ALA.
There is an interesting article saying accumulation of citrate may be dangerous for TNBC in hypoxic condition.
Thank you for the article. I went through it and I find it interesting indeed.
We know that Citric Acid accumulation, at a high level, will trigger glycolisis inhibition via a feedback mechanisms. This has been discussed here https://www.cancertreatmentsresearch.com/citric-acid-inhibits-fermentation-and-kills-cancer-in-humans/ and here https://www.cancertreatmentsresearch.com/drugs-and-supplements-that-block-fermentation-and-help-fight-cancer/.
From this point of view, most of the literature suggests that Citric Acid will have anti cancer effects.
However, the reality is never black or white. And this is why I thought and discussed here https://www.cancertreatmentsresearch.com/citric-acid-inhibits-fermentation-and-kills-cancer-in-humans/ the fact that whenever we use Citric acid as an anti-cancer effect we should also use an ATP citrate lyase inhibition and other possible Melavonate pathway inhibitors.
ATP citrate lyase inhibition has been discussed in the article above while Melavonate pathway inhibitors have been discussed here https://www.cancertreatmentsresearch.com/cholesterol-lowering-statin-drugs-to-fight-cancer/ and here https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/.
Why I suggested the above, is because I can imagine that Citrate accumulation, before reaching the level required to switch-off glycolisis may trigger upregulation of mevalonate pathway, that is supporting cancer growth via different mechanisms discussed e.g. here https://www.cancertreatmentsresearch.com/cholesterol-lowering-statin-drugs-to-fight-cancer/
This is how I can integrate the results published in the paper you shared here with the mechanisms I am aware off. Therefore, although it’s only one paper, the paper you shared indicates that I should stay with my view in which Citric Acid used in high dose should be combined with Statins (melavonate pathway inhibitors) and HCA (ACLY inhibitors), so that is less likely that Citrate will fuel lipid metabolism. Off course, IF we succeed to put together a strong strategy that will inhibit respiration and fermentation and deplete ATP, I would not be worried about fuelling lipid metabolism.
Also, I received your e-mail and I will respond asap.
Your note makes sense. While excess citrate may be necessary to switch off gloycolysis, my assumption is that HCA & Statin can be used just on their own w/o citrate supplements. Is this thought correct?
If HCA inhibits Citrate->Acetyl-CoA and Statin inhibits Acetyl-Coa => Mevalonate pathway, the remaining paths unblocked here are 1) Citrate -> Pyruvate, and 2) Acetyl-Coa -> Acetylation if I am correct
For 1), would HCA direct Citrate toward Pyruvate? and could that be possible resisting mechansim? I don’t think I have seen anything on this path. Let me know if I am wrong.
For 2) Also, if statin successfully (in theory) blocks MEvalonate pathway in part, would more Acetylation be a problem?
Thanks for the very good questions.
HCA and Statin can just be used on their own as discussed here https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/ and here https://www.cancertreatmentsresearch.com/cholesterol-lowering-statin-drugs-to-fight-cancer/
Adding Citrate could make sense next to HCA and Statin. But as stated in the reference you shared above, increase of intracellular Citrate may lead to activation of the AKT/ERK/MMP2/9 signaling axis. The authors did not know how to explain that, when the paper was published.
Here is how I could think of explaining that:
1. Before reaching the levels to inhibit glycolisis, Citrate gradually increases inside the cell.
2. If ACLY is not inhibited by HCA or other inhibitors, part of that Citrate converts into Acetyl-COA and that leads to an increase in the fuel going to the Melavonate pathway
3. As discussed shortly here https://www.cancertreatmentsresearch.com/cholesterol-lowering-statin-drugs-to-fight-cancer that will increase several important metabolites, including Farnesyl PyroPhosphate (FPP) and GeranylGeranyl PyroPhosphate (GGPP)
4. This in turn will have direct impact on Rho and Ras proteins
5. Ras and Rho are locate upstream AKT and ERG so they will be immediately influenced activating growth and migration signals
Of course this would have to be verified in the lab.
So in my view, if there is a danger, that is not related to Citrate accumulation due to ACLYL inhibition by HCA and/or Mevalonate pathway inhibition by Statins – since that will lead to inhibition of the growth and migration signals. Instead, the danger may come whne Citrate accumulates while ACLYL works normally and Mevalonate is upregulated.
Otherwise, I do not see other major mechanism to represent a danger. But in any-case, to further reduce any possible danger, along the lines you mentioned, I would probably
– add a mithochondria inhibitor (such as Metformin) to address 1)
– ACLY inhibition should address 2) as it also reduce Acetyl-COA required for acetylation – here we have a nice discussion on it’s position inside the cell https://www.sciencedirect.com/science/article/pii/S0223523418307736
A HDAC inhibitor (such as Valproic Acid or Sodium butyrate) and HAT inhibitor (such as high dose Curcumin) in parallel to Citrate supplementation could be extra helpful.
Finally, I should say, that most literature suggests Citrate may be a good anti cancer tool. Combined with Statins, HCA, Metformin should be even stronger.