Cholesterol is a lipid molecule present in the membranes of all mammalian cells and is essential for their growth and viability. As an indispensable constituent of plasma membranes, cholesterol affects properties and functions of membrane proteins such as receptors, enzymes, or ion channels.
Cells produce cholesterol or are able to draw it from extracellular sources via the LDL receptor (e.g. from diet). Cholesterol produced inside the cell is based on acetyl coenzyme A (acetyl-CoA) which in turn is usually produced out of Citrate coming out of mitochondria (Ref.). The endoplasmic reticulum (ER) serves as the major site of cholesterol synthesis via a relatively complex process (Ref.). Note that when cancer cells are deprived of essential nutrients they may also produce acetyl-CoA from acetate (Ref.).
Fast dividing cancer cells need cholesterol to build and maintain the viability of their membranes and finally divide. In order to have that cholesterol available when needed they store cholesterol as cholesteryl esters inside the cell (as cytoplasmic lipid droplets). To do this, cells need to use an enzyme called ACAT1 (acyl-coenzyme A (CoA):cholesterol acyltransferase), that converts cholesterol in its form that can be stored i.e. cholesteryl esters. Reducing or inhibiting this enzyme will directly impact the potential for division of aggressive cancers.
ACAT1 , is expressed highly in macrophages, adrenal glands, sebaceous glands, and steroidogenic tissues, is also expressed in atherosclerotic lesions (Ref.) As a result, ACAT1 inhibition was a subject specifically studied because that was expected to reduce atherosclerotic lesion development by reducing intestinal cholesterol absorption, lowering plasma cholesterol levels, and by directly inhibiting macrophage foam cell formation in atherosclerotic lesions (Ref.).
In cancer, the role of ACAT1 has been brought only recently under the spot light, an it is now recognized as an important element for the fast developing cancers:
- Prostate cancer: “The length of time patients retained stable prostate-specific antigen levels after cancer therapy (biochemical progression-free survival) was significantly shorter in patients with high ACAT1 expression. Further, high expression of ACAT1 was associated with shorter disease-free survival (period after successful treatment in which there is no appearance of the symptoms or effects of the disease).” (Ref.)
- Pancreatic cancer: it has been recently shown that depletion of cholesterol esterification significantly reduced pancreatic tumor growth and metastasis in mice. (Ref.) Findings also showed that blocking storage of cholesteryl ester causes cancer cells to die, specifically due to damage to the endoplasmic reticulum, a workhorse of protein and lipid synthesis. The researchers, founded Research Therapeutics LLC to work toward developing a formulation of an ACAT inhibitor for human cancer patients.
- Breast cancer: Acyl-CoA:cholesterol acyl transferase (ACAT1) is highly expressed in human breast cancer cell lines and ACAT inhibition reduces proliferation. Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: a molecular and clinicopathological study (Ref.)
- Adrenal cancer: ATR-101 is the company’s novel, oral drug candidate in a Phase 1 clinical study for the treatment of adrenocortical carcinoma (ACC). ATR-101 is a selective inhibitor of ACAT1, which reduces adrenal steroids and induces apoptosis of cells derived from the adrenal cortex. (Ref.). Actually the only drug specifically used to kill, inhibit or slow down the adrenal cancer cells, Mitotane, is an ACAT1 inhibitor and this was only very recently discovered (Ref.)
- Virtually All cancer: “We revealed a cancer-specific accumulation of cholesteryl ester in multiple malign cancers, including prostate, pancreatic, lung, colon and leukemia, mediated by the enzyme acyl-CoA cholesterol acyltransferase-1 (ACAT-1). Inhibition of ACAT-1 significantly suppressed tumor growth and metastasis in mouse models. ACAT-1 inhibition was found to induce endoplasmic reticulum stress and apoptosis in cancer cells.” (Ref.)
This sis why I think that when treating fast developing tumors, ACAT1 is one of the enzymes we need to address and inhibit.
Note that recently it has been published an article indicating that Heparin may lead to lipid droplet inhibition, via a mechanism other than ACAT1 inhibition. This is yet another element supporting the anti cancer potential of Heparin (Ref.).
ACAT1 inhibitors may also improve the Immune System and Immunotherapies (Ref.).
When cells require additional cholesterol, they express high levels of LDL receptors and the intracellular cholesterol production pathway (via HMG-CoA reductase). Plasma low-density lipoprotein is the vehicle that transports cholesterol (and cholesteryl ester) to the cell. Free cholesterol is removed from the tissue by high-density lipoprotein (HDL) and transported to the liver to be eliminated from the body.
As cellular levels of free cholesterol rise, LDL receptor levels and the intracellular cholesterol production pathway activity are suppressed and ACAT1 enzyme is activated in order to store excess cholesterol as cholesteryl esters. In other words, high intracellular free cholesterol inhibits the intracellular cholesterol production pathway (and specificallyHMG-CoA reductase) and LDL receptors (Ref.). While in cancer cells cholesteryl esters may be found in large amounts, in most normal cell types, cholesteryl esters are present only in low levels, mainly as cytoplasmic lipid droplets.
Here are a few examples on how the cholesterol biosynthesis pathway looks like:
- An overview of the cholesterol biosynthesis pathway https://openi.nlm.nih.gov/detailedresult.php?img=PMC2241839_1471-2407-7-223-3&req=4
- lipid biosynthetic pathways http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820259/figure/f1-0061353/ and on Research gate higher resolution
Virtually every cell is capable of cholesterol synthesis.
(In plasma, cholesteryl esters are part of the neutral lipid cargo present in the intestinal chylomicrons and in the hepatic very low-density lipoproteins (VLDL). In steroidogenic tissues such as adrenals, cholesteryl esters serve as the cholesterol reservoir for producing steroid hormones. In the disease atherosclerosis, chronic accumulation of cholesteryl esters in macrophages causes these cells to appear foamy and is a hallmark of early stages in atherosclerosis.)
In cancer cells, ACAT1 has yet another important role besides cholesteryl esters storage. Indeed, it has been suggested that fibroblasts, with mitochondrial dysfunction, produce ketone bodies in the tumor stroma. These ketone bodies are imported via the MCT1 transporter (same transporter importing lactate and 3BP) and re-utilized by adjacent cancer cells, which process these ketone bodies as mitochondrial fuels for oxidative phosphorylation (OXPHOS), to drive anabolic tumor growth. In order to process ketone bodies, the expression of certain neuron-specific enzymes in cancer cells, such as ACAT1/2 would be required. (Ref.)
The ACAT1 enzyme has a few unique properties:
- First, it is activated by potassium ions binding near the CoA binding site and the catalytic site.
- ACAT1 enzyme activity/expression is enhanced by leptin, angiotensin II (Ref.), and insulin in human monocytes/macrophages. Actually, this reminds me that Losartan, an angiotensin II receptor antagonist has good anticancer profile (Ref.)
Note that ACAT is also known as also known as sterol O-acetyltransferase, or SOAT1.
Note that there is also an enzyme called ACAT2 which condenses two acetyl-CoA into acetoacetyl-CoA, just at the beginning of the Mevalonate pathway (that converts acetyl-CoA into cholesterol and a few other products. This is the pathway that is targeted by statins, the cholesterol lowering drugs which also have anti cancer effects (Ref.) and will be discussed in another post.
Now, the questions is what are the drugs or supplements available and capable to modulate ACAT. Here is what I know so far:
Avasimibe: One of the very few drugs developed to inhibit ACAT 1 was Avasimibe. Avasimibe had made it to phase 3 trials for cardiovascular disease, but the pharmaceutical giant Pfizer discontinued its development about 10 years ago. Internal drug interaction research apparently showed that Avasimibe weakened the effect of Lipitor, Pfizer’s leading cardiovascular drug, when it had instead been meant to boost lipitor and be taken alongside it. –> not accessible
Rimonabant: an anorectic antiobesity drug that has been withdrawn from the market due to potentially serious side effects. It is a dual inhibitor of acyl CoA:cholesterol acyltransferases 1 and 2. http://www.ncbi.nlm.nih.gov/pubmed/20609360 –> not accessible
ATR-101, a Selective ACAT1 Inhibitor in Development for Adrenocortical Carcinoma, Disrupts Steroidogenesis and Causes Apoptosis in Normal Canine Adrenals http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.AHPAA.11.OR14-5#sthash.Zu7l9qzk.dpuf. This drug is currently in clinical trials –> not accessible
Docosahexaenoic acid (DHA): A recent study suggested that DHA, omega-3 fatty acid, might directly bind and (weakly) inhibit ACAT1 http://www.ncbi.nlm.nih.gov/pubmed/19217763
Honokiol: a natural extract from magnolia which has strong anticancer effects and which I specifically like a lot http://europepmc.org/abstract/MED/9434609
Magnolol: another extract from magnolia has also been shown to act as a natural inhibitor to acyl-CoA: cholesterol acyltransferase (ACAT).
Saururus chinensis root: contain saucerneol B and manassantin B for inhibiting ACAT activity. Saucerneol B inhibited hACAT-1 and hACAT-2 with IC50 values of 43.0 and 124.0 μΜ, respectively, whereas manassantin B inhibited hACAT-1 and hACAT-2 with IC50 values of 82.0 μΜ and only 32% inhibition at 1 mM, respectively https://www.google.com/patents/WO2013019932A1?cl=en&dq=acat1&hl=en&sa=X&ei=DD2jVJ-eOeP8ygPUloHACA&ved=0CEsQ6AEwBg
Sophora flavescens: Human ACAT Inhibitory Effects of Flavonoids from Sophora flavescens http://www.koreascience.or.kr/article/ArticleFullRecord.jsp?cn=JCGMCS_2008_v29n11_2287
The following patent suggests a long list of ACAT inhibitors of which betulinic acid, honokiol, magnolol, ginseng saponins are the most accessible http://www.google.com/patents/WO2013171100A1?cl=en
Piperine: was found to inhibit both ACAT1 and ACAT2 isozymes to a similar extent (IC50: 16, 18 microM, respectively) in cell-based assays using ACAT1- or ACAT2-expressing cells. http://www.ncbi.nlm.nih.gov/pubmed/18520030 also suggested as potential treatment for obesity-related diseases http://pubs.acs.org/doi/abs/10.1021/jf204514a?src=recsys&journalCode=jafcau
Hespertin: was found to inhibit both ACAT1 and ACAT2 (Ref.)
Sulfasalazine: A cheap drug that is used in the management of inflammatory bowel diseases found as an ACAT1 inhibitor (Ref.)
Ezetimibe: an anti-hyperlipidemic medication which is used to lower cholesterol levels found as an ACAT1 inhibitor (Ref.)
Conclusion on the ACAT inhibitors: the most interesting and accessible ACAT inhibitors so far are Piperine, Honokiol and DHA, all natural extracts available online as supplements, accessible to all and with known anti cancer potential behind ACAT inhibition. The nice fact about these three is that based on their potential I would anyway take them even if they would not have ACAT1 inhibiting activity (Piperine specifically in combination with e.g. Curcumin to increase its bio availability).
Piperine: The usual recommended dose of piperine is 5-15 mg/day. It is absorbed quickly and well from the digestive tract. Effects on absorption of other substances begin around 15 minutes after dosing and last for an hour or two. Blood levels peak about 1-2 hours after dosing but effects on metabolic enzymes can last much longer – from one to many hours, depending upon the enzyme type. (Ref.) For anti cancer effects I would go beyond that.
Honokiol: The anticancer recommended dose is 3g to 5g/day (Ref.)
DHA: Fish oil containing DHA at several grams/day
DHA: available online – I do not have a favorite source and I would appreciate suggestions
Acyl-coenzyme A:cholesterol acyltransferases http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711667/
Cholesteryl Esters: Fueling the Fury of Prostate Cancer http://www.sciencedirect.com/science/article/pii/S1550413114000680
ATR-101, a Selective ACAT1 Inhibitor in Development for Adrenocortical Carcinoma, Disrupts Steroidogenesis and Causes Apoptosis in Normal Canine Adrenals http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.AHPAA.11.OR14-5#sthash.Zu7l9qzk.dpuf
ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs. http://www.ncbi.nlm.nih.gov/pubmed/26986192
ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase-3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis.
ACAT1/SOAT1 as a therapeutic target for Alzheimer’s disease. http://www.ncbi.nlm.nih.gov/pubmed/26669800
Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: a molecular and clinicopathological study. http://www.ncbi.nlm.nih.gov/pubmed/26055977
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