Update 03 September 2018: Today I became aware of a recent (2017) scientific paper published in Nature magazine, one of the most prestigious and high impact magazine, discussing work on Citric Acid performed at Harvard School of Medicine, and concluding the following: “Our data suggests that citrate can inhibit tumor growth in diverse tumor types and via multiple mechanisms. Dietary supplementation with citrate may be beneficial as a cancer therapy.” (Ref.) Given the fact that this work was performed by a world leading medical school and published in a world leading scientific magazine, I see this as a strong support for the work of Dr. Alberto Halabe Bucay reporting response in various cancer patients (see below), work which I have questioned before. I’ve also wrote a short update post here.
Citric acid exists in large amounts in a variety of fruits and vegetables, most notably citrus fruits and was first time isolated from lemon juice. Its salt form, Citrate, is an intermediate in the citric acid cycle (also called TCA cycle, TriCarboxylic Acid cycle, Krebs cycle, Szent-Györgyi – Krebs cycle), a central metabolic pathway for animals, plants and bacteria.
In others words, Citrate is a major product of mitochondria, the engine of the cell. When there is to much Citrate going out of the engine, it means there is enough energy produced by the engine and a feedback mechanism will “talk” to the glycolisis (Ref.), the path through which fuel is provided to the engine, and ask to reduce the amount of fuel. As a result, the more Citrate builds up in the cell, the more the cell will think it has enough of what it needs and will reduce or even shut down the glycolisis process.
Since glycolisis (or fermentation) is essential in most cancers to obtain various elements required for the survival of the cancer cells (e.g. fast energy production, anti-oxidants, etc.), glycolisis inhibition may directly lead to the eradication of cancer cells. Inhibiting glycolisis will also lead to a lower amount of acidity produced and exported by the cancer cells and thus a better tumor environment in which the immune system (T cells) will reactivate (Ref.) or chemo therapies can go through without being deactivated (protonated). From this point of view, I would expect that Citrate can both work alone but also enhance chemo therapy (Ref.) and immunotheraphy.
From a scientific point of view, the inhibitory effect of glycolisis triggered by Citrate is well understood and recognized (see references in the Mechanism section and Reference section). So there is no question about that. This is why Citrate has been indeed proposed as an anti cancer agent. However, the questions is whether the same theoretical and laboratory results can be achieved in humans.
Interestingly, Dr. Alberto Halabe Bucay in Mexico, was one of the few proposing and using Citric Acid to treat and cure cancer patients so far. While Dr. Alberto reports are typically very short, of anecdotal stile, the results emerging out of that indicate that in some advanced cancer patients Citric Acid used as stand alone therapy may lead to tumor regression in patients with various tumor types. His number of published case reports is truly impressive to me. Yet, it is a pitty to see the anecdotal stile of the published reports as they are difficult to judge. Here is Dr. Alberto’s Twitter account where he is constantly sharing links to new published successful cases: https://twitter.com/Cancercuretop2, and here is the Facebook page https://www.facebook.com/alberto.halabebucay
Off course, the questions that remains open to me is how many patients were treated with Citric Acid to get to those successful cases reported.
Update 25-02-2017: If Dr. Alberto would be the only one to claim curing cancer patients with Citric Acid, the story would not stand so strong and more evidence would be required. Yet, one of the contributors on this website (thank you Dr. Helga) has recently pointed out that Citric Acid has been used successfully against cancer since 1866 and reported at that time in the respectable scientific journal “British Medical Journal” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2309166/pdf/brmedj05661-0005.pdf
So what we have here is an element that is cheap, safe, easy to administrate (orally), accessible, with acceptable theory regarding the anti cancer mechanism and as Dr. Alberto Halabe Bucay and those before him suggested, relevant in various types of tumors.
However, it is my personal opinion that Citric Acid comes with a risk as well. This is just my theory, and that is due to the fact that it may also represent a fuel for cancer cells out of which some cancer cells may produce cholesterol, much needed for fast cellular division and hormone production. To reduce or eliminate this risk, as discussed below, I would always combine Citric Acid with a Statin and HCA. These drugs/supplements will not only reduce this risk but also are drugs/supplements with well known anti cancer effect as well.
Funny enough, while writing the end of this article I realize it now may make scientific sense to drink lemon juice in order to kill cancer (see the estimations on how much lemon juice or grapefruit juice we would need to drink daily, in the Source section of this post). I never believed this is possible before, but now, based on all these references and mathematics, it may makes sense. Note: Lemonade therapy is also suggested / used in hospitals as a therapy to address kidney stone formation / nephrolithiasis (Ref.1, Ref.2, Ref.3)
Results in Humans:
There are various case reports, nearly all from Dr. Halabe, indicating Citric Acid is effective against various forms of cancer, in humans:
Hypothesis proved…citric acid (citrate) does improve cancer: A case of a patient suffering from medullary thyroid cancer
A patient with Glioblastoma Multiforme who improved after taking citric acid orally
A Comment to the Article Published in the APJCP by Choi and Co-workers about the Treatment of Cancer with Citric Acid
Effects of sodium citrate on proliferation and apoptosis of ovarian cancer cells
Case Report: A Patient With Pancreatic Cancer Who Improved After the Treatment with Citric Acid That She Received
A Patient with Metastatic Colon Cancer who Improved after the Treatment with Citric Acid that He Received.
Pathological report of a patient with cancer of the esophagus improved considerably after receiving citric acid orally
Remission of multiple myeloma after receiving only citric acid orally
A PATIENT WITH ENDOCRINE HEPATIC TUMOR WHO IMPROVED AFTER TAKING CITRIC ACID ORALLY
Case Report: A Patient With Invasive Bladder Cancer Who Improved After The Treatment With Citric Acid That He Received
Effect of citrate on malignant pleural mesothelioma cells: a synergistic effect with cisplatin.
Here are some more anecdotal reports: https://cancerfighter.wordpress.com/2011/03/15/more-news-on-citric-acid-therapy-for-cancer/
However, since I wrote this article, two visitors of this website (both Lung Cancer stage IV) who tried Citric Acid are reporting no improvements after one or two months of Citric Acid usage:
Therefore, the wide effectiveness of Citric Acid against various forms of cancer has still to be demonstrated by sources other than Dr. Halabe.
Citrate is a key intermediate in both catabolism and anabolism and occupies a prominent position in cell energy metabolism. There are two sources of intracellular citrate:
1. Citrate is produced inside the mitochondria within the Krebs cycle. When the cell has excess energy, citrate is transported out of the mitochondrial matrix across the inner membrane via the mitochondrial citrate transport protein (CTP). In the cytoplasm, is then broken down by the ACLY (ACL) enzyme into
- for fatty acid synthesis and
- cholesterol production
- to be converted back to pyruvate and enter mitochondria again
This process is depicted in this picture https://www.cancertreatmentsresearch.com/?p=913 and this one http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348998/figure/F1/
High concentrations of cytosolic citrate can inhibit phosphofructokinase, one of the most important control “knob” in the mammalian glycolytic pathway. A high level of citrate means that biosynthetic precursors are abundant and additional glucose should not be degraded for this purpose (Ref.)
Therefore, high concentrations of citrate will inhibit the conversion of fructose 6-phosphate, into its next step in glycolysis, i.e. fructose 2,6-bisphosphate (F-2,6-BP).
Interestingly, a fall in pH also inhibits phosphofructokinase activity (Ref.) representing a link between the cancer treatment strategy focused on cancer cell acidification I discussed in another post (Ref.) and glycolisis inhibition.
Obviously, the inhibition of glycolisis is highly relevant in cancer cells and it can lead to cancer cell death. Indeed this fact has been demonstrated in several papers (please see the Reference section).
2. Citrate is not only produced by mitochondria but can also be taken up from blood through PMCT plasma membrane transporters (Ref.) or the so called NaCT (Ref.). Because NaCT is more activated in the acidic environments (Ref.1, Ref.2), cancer cells may absorb higher levels of Citrate compared to normal cells.
Here is a good reference to get a better feeling on the above processes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913483/
As a side note, Prostate gland, is known to produce and release large amounts of citrate during its normal secretory function. (Ref.) This may be a reason why not to use Citric Acid for prostate cancer and possibly other cancers of hormone producing cells.
Other anti cancer effects of Citrate may be related with its capability to promote acetylation of histones, to inhibit tumor angiogenesis and other potential mechanism (Ref.)
Citrate also causes anticoagulation by chelation of calcium, and is likely to lead to magnesium chelation as well. (Ref.)
Citric Acid seems to also inhibit pyruvate dehydrogenase (PDH): “Citrate inhibits the interconversion of the inactive form of pyruvate dehydrogenase to the active form of the enzyme.” (Ref.) I did not know this, and if this is true, Citrate should not be used with DCA since the whole point of DCA is to re activate PDH by inhibiting PDK https://www.cancertreatmentsresearch.com/dichloroacetate-dca-treatment-strategy/
In other words, if the results presented in this paper are true, when using Citrate + DCA we may need to make a choice between the use of DCA and that of Citrate since DCA will try to activate PDH while Citrate will inhibit PDH. If Citrate indeed inhibits PDH, I expect Citrate will win the fight since it may act directly on PDH while DCA acts indirectly through PDK.
Citrate also inhibits Citrate Synthase, an enzyme acting the first step of the citric acid cycle (or Krebs cycle):
The inhibition of PDH and Citrate Synthase by Citrate, indicates that Citrate may not only interfere with glycolisis but also mitochondria function in cancer cells.
Dose & Administration:
Although there are publications suggesting sodium citrate as an anti cancer element too, Dr. Alberto insists in using Citric Acid only as that was clearly demonstrated to be effective.
The daily dose seems to be min 4g/day and up to 30g/day. Yet 4g to 8g/day seems the most common dose used by Dr. Alberto.
It has been claimed to be completely safe. It is recommend to be combined with juices or meals (as powder or capsules). Some people are taking it with antacids like omeprazole to reduce the GI side effects.
Start with 500mg 3x/day and move up to the target dose of for example 10g/day.
Some more ideas for its application:
- In order not to have Citrate converted to acetyl-CoA, and also to build up faster Citrate in the cytosol, inhibit ACYL with HCA (https://www.cancertreatmentsresearch.com/?p=956). That means, it may be wise to add HCA capsules (1. to 3 g/day) during Citrate administration.
- In case Citrate is still converted to acetyl-CoA even if HCA is used, use Statins (FDA approved drugs) to inhibit further cholesterol production
- It may also be wise to target and slow down mitochondria during Citrate administration with e.g. Metformin, Doxycicline, etc.
- Update 25-02-2017: Interesting enough, it has previously suggested that DCA, another well known anticancer drug, can induce the accumulation of high level of citrate inside the cytoplasm and with that inhibit glycolisis (Ref.). Therefore, a good addition to the Citric Acid treatment may be DCA.
- Update 30-March-2017: According to additional info I came across and shared as an update in the “Mechanism” section, it doesn’t make sense to add DCA to Citric acid since DCA will try to reactivate PDH while Citric acid will inhibit that. Therefore, based on the latest info, I would not use CA+DCA at the same time but try one for longer time, if I would see progression I would switch to the other. So maybe one month try and observe the markers?
Actually, if I think more, due to the ACLY over activation in many cancers (Ref.), I would not take Citrate without inhibiting Citrate conversion to acetyl-CoA with ACLY inhibitors. Therefore, I would always use HCA supplements when on Citrate therapy. I would also use a Statin (preferably lipophilic) to make sure the cholesterol production will be limited while on CA. Specifically, hormone producing cells such as prostate cells are very capable to convert Citrate into acetyl-CoA as they typically have to do that in order to obtain the cholesterol required for hormone production (Ref.). Note: I read somewhere that Metformin may also downregulate ACLY but cannot find the reference right now.
Because Citarte is transported inside the cells by a Na coupled transporter (Ref.), I guess table salt may enhance Citrate absorption.
Update 27-02-2017: Ergin, one of the contributors on this website, has recently pointed out a relevant paper http://file.scirp.org/Html/6-2700957_37559.htm This paper suggest (but is not totally clear) that CA may boost gluconeogenesis (that is different than glycolisis) leading to a high glucose level in the blood. If this is true, it is something we do not want. So what we can do about it?
First, anyone who is using CA can measure his blood glucose levels using a typical measurement toll that can be used to measure glucose at home. If indeed, the glucose levels are increasing after CA, what I would do is to always use Metformin before CA administration. That is because Metformin is an inhibitor of the gluconeogenesis.
As a result of our discussions so far, to address the potential weak spots of CA treatment, I would combine CA treatment with Metformin (500mg) and HCA (500-1000mg) (both ingested about 30 min prior to taking CA). Metformin would address potential increase of gluconeogenesis by CA, and HCA will address potential conversion of CA in cholesterol and other fuels for cancer via the potentially upregulated mevalonate pathway as previously discussed.
There is a good amount of scientific evidence suggesting that both HCA and Metformin have good potential against cancer. As a result, including the two will only increase the chance of success.
Update 28-02-2017: Following our discussion on the potential increase in blood glucose level after taking CA, I did check if there is any such increase in my case. I mixed 4g of CA with water and took that at once. Measured blood glucose once before taking CA and a few times after, at 5min, 30min and one hour. During this time, there was no specific increase of the blood glucose.
This may be specific to my case, so others may want to check for themselves, but these results are not supporting the claims in the article http://file.scirp.org/Html/6-2700957_37559.htm Yet, everyone should check this for himself. Based on this result, Metformin would not be necessarily required when using CA but I would probably use it anyway given its important benefits in cancer.
Update 01-07-2017: Here is a relevant questions https://www.cancertreatmentsresearch.com/another-weak-spot-of-many-cancer-cells-atp-citrate-lyase-inhibition/#comment-5155 and a relevant answer to that that I thought may be good to add it here too:
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/), which is what CA may do, we also need to make sure we inhibit or reduce PPP or alternatively the activity of mithocondria (with e.g. Metformin) 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
Safe but here are some attention points:
Contraindicated in severe renal impairment with oliguria or azotemia, untreated Addison’s disease, adynamia episodica hereditaria, acute dehydration, heat cramps, anuria, severe myocardial damage, and hyperkalemia from any cause. (Ref.)
Large doses may cause hyperkalemia and alkalosis, especially in the presence of renal disease. Concurrent administration of potassium-containing medication, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, or cardiac glycosides may lead to toxicity. (Ref.)
Academic investigations are currently running focused on limiting absorption of Citrate as this approach might mimic caloric restriction, decrease fatty acid and cholesterol biosyntheses, prevent obesity, and extend life-span (Ref.). Consequently, long term use of Citric Acid may be detrimental.
It can be found everywhere including at iHerb: http://www.iherb.com/Now-Foods-Citric-Acid-100-Pure-Powder-1-lb-454-g/27028
It can also be obtained from the lemon or lime juice but also from other sources:
- The juice of lemons and limes squeezed from the fruits contained the most citric acid (48 and 46 g/L, respectively) (Ref.)
- Grapefruit juice and orange juice from ready-to-consume, 100% juice formulations contained 25 and 17 g/L, respectively. Orange juice squeezed directly from oranges had a lower citric acid content than ready-to-consume orange juice. (Ref.)
So based on the above it seems that in order to ingest e.g. 10g of citric acid/day we need to drink about 250ml lemon juice. This seems feasible to me and offcourse, I would drink this mixed with water during one day. Alternatively, I would drink about 500ml of grapefruit juice daily, which I think is very easy to achieve. What is not clear to be yet is the bio availability difference between using the fruit as a source or the commercially available powder.
Funny enough, I now realize that with this article and the enclosed references it now makes scientific sense to drink lemon juice in order to kill cancer. I never believed this is possible before, but now, based on all these references and mathematics, it makes sense. 🙂
Phosphofructokinase 1 glycosylation regulates cell growth and metabolism http://www.ncbi.nlm.nih.gov/pubmed/22923583
Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention.
Glycolytic enzyme inhibitors effectively kill cancer cells http://www.herbalzym.com/2012/09/glycolytic-enzyme-inhibitors-effectively-kill-cancer-cells-part-2/
Metabolic quirks yield tumour hope http://www.nature.com/news/metabolic-quirks-yield-tumour-hope-1.15005
Citric Acid Induces Cell-cycle Arrest and Apoptosis of Human Immortalized Keratinocyte Cell Line (HaCaT) via Caspase- and Mitochondrial-dependent Signaling Pathways http://ar.iiarjournals.org/content/33/10/4411.abstract?etoc
Citric acid is an alpha-hydroxyacid (AHA) widely used in cosmetic dermatology and skincare products. However, there is concern regarding its safety for the skin. In this study, we investigated the cytotoxic effects of citric acid on the human keratinocyte cell line HaCaT. HaCaT cells were treated with citric acid at 2.5-12.5 mM for different time periods. Cell-cycle arrest and apoptosis were investigated by 4,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining, flow cytometry, western blot and confocal microscopy. Citric acid not only inhibited proliferation of HaCaT cells in a dose-dependent manner, but also induced apoptosis and cell cycle-arrest at the G2/M phase (before 24 h) and S phase (after 24 h). Citric acid increased the level of Bcl-2-associated X protein (BAX) and reduced the levels of B-cell lymphoma-2 (BCL-2), B-cell lymphoma-extra large (BCL-XL) and activated caspase-9 and caspase-3, which subsequently induced apoptosis via caspase-dependent and caspase-independent pathways. Citric acid also activated death receptors and increased the levels of caspase-8, activated BH3 interacting-domain death agonist (BID) protein, Apoptosis-inducing factor (AIF), and Endonuclease G (EndoG). Therefore, citric acid induces apoptosis through the mitochondrial pathway in the human keratinocyte cell line HaCaT. The study results suggest that citric acid is cytotoxic to HaCaT cells via induction of apoptosis and cell-cycle arrest in vitro.
The biological significance of cancer: mitochondria as a cause of cancer and the inhibition of glycolysis with citrate as a cancer treatment. http://www.ncbi.nlm.nih.gov/pubmed/17368752
In this article, I present the hypothesis that cancer presents due to the domination of the cell by mitochondria, which, from an evolution viewpoint, appeared in multi-cellular living being with the incorporation of a bacteria into a primitive cell, the bacteria sustained itself as mitochondria and these conserved their identity and bacterial characteristics, based on this, the hypothesis is suggested of the biological competition between the cell and the mitochondria; the mitochondria, on establishing itself as an independent entity within the cell, created the need to permanently remain in the cytoplasm of the cell, thus, from an energy viewpoint, when a cell becomes malignant, the mitochondria are the sole beneficiaries, as there is an ideal environment at the cellular level for the mitochondria to sustain their functions, and from this hypothesis, the treatment for fighting cancer consists of inhibiting glycolysis, being the principal source of energy for the mitochondria, this is achieved by administering citrate to cancer patients, as the citrate inhibits the phosphofructokinase enzyme, the pyruvate dehydrogenase complex and the succinate dehydrogenase enzyme of Krebs cycle, thus, the mitochondria will be forced to limit their metabolism and, secondarily, will lower the reproduction capacity of the cell in general.
Inhibition of Mcl-1 expression by citrate enhances the effect of Bcl-xL inhibitors on human ovarian carcinoma cells. http://www.ncbi.nlm.nih.gov/pubmed/24103422
The inhibition of two major anti-apoptotic proteins, Bcl-xL and Mcl-1, appears essential to destroy chemoresistant cancer cells. We have studied their concomitant inhibition, using ABT 737 or siRNA targeting XL1 and citrate, a molecule which reduces the expression level of Mcl-1.Two cisplatin-chemoresistant ovarian cell lines (SKOV3 and IGROV1-R10) were exposed to ABT 737 or siRNA targeting XL1 and citrate at various individual concentrations, or combined. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways.Mcl-1 expression was barely reduced when cells were exposed to citrate alone, whereas a mild reduction was observed after ABT 737 treatment. Concomitant inhibition of Bcl-xL and Mcl-1 using ABT 737 or siXL1 associated with citrate was far more effective in inhibiting cell proliferation and inducing cell death than treatment alone.Given that few, if any, specific inhibitors of Mcl-1 are currently available, anti-glycolytic agents such as citrate could be tested in association with synthetic inhibitors of Bcl-xL.
Citrate Induces Apoptotic Cell Death: A Promising Way to Treat Gastric Carcinoma? http://ar.iiarjournals.org/content/31/3/797.full
Gastric carcinoma is frequent, particularly in China, and therapy is often inefficient. Because cancer cells are partly or mainly dependent on glycolysis to generate adenosine triphosphate ATP (Warburg effect) and/or to produce precursors (of lipid, nucleotides, etc.) for building new cells, any inhibition of glycolysis may slow down the cell proliferation and/or may kill cells. The antitumor effect of citrate, an anti-glycolytic agent inhibiting phosphofructokinase (PFK) was tested on two human gastric carcinoma cell lines. Materials and Methods: Cell viability and morphology were assessed after 24-72 h exposure to citrate (5, 10, 220 mM). Apoptosis was assessed by annexin V-FITC/PI staining and Western immunobloting. Results: A 3-day continuous exposure to citrate led to near destruction of the cell population in both cell lines, apoptotic cell death occurred through the mitochondrial pathway in a dose- and time-dependent manner, associated with the reduction of the anti-apoptotic Mcl-1 protein in both lines. Conclusion: Citrate demonstrates strong cytotoxic activity against two gastric cancer lines, leading to an early diminution of expression of Mcl-1 and to massive apoptotic cell death involving the mitochondrial pathway.
PROPOSAL: DEVELOPMENT OF A PROTOCOL BASED ON CLINICAL EXPERIENCE WITH PATIENTS WITH CANCER WHO HAVE IMPROVED AFTER TAKING CITRIC ACID ORALLY http://www.worldwidejournals.com/indian-journal-of-applied-research-(IJAR)/articles.php?val=Njg4MQ==
The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target. https://www.ncbi.nlm.nih.gov/pubmed/27912843
Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy. Strategies aiming to increase cytosolic citrate should be developed and tested in humans, knowing that experimental studies have shown that administration of citrate and/or inhibition of ACLY arrest tumor growth, inhibit the expression of the key anti-apoptotic factor Mcl-1, reverse cell dedifferentiation and increase sensibility to cisplatin.
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