Fatty Acid Synthase [FAS, FASN] is an enzyme used in the synthesis of fatty acids - mainly palmitic acid, a 16-carbon saturated fatty acid.
I mentioned palmitic acid in recent posts. It is the preferred energy source of normal prostatic epithelial cells, & this mostly does not change in cells that become cancerous. Palmitic acid is a saturated fat found not only in animal fat, but vegetable fats & in the fat of high-carb vegetarians (excess carbs are converted to palmitic acid.)
It might have seemed from my posts that we are doomed. Palmitic acid is the starting point in the body for the production of fatty acids with longer carbon chains. There are many specialized fatty acids & the body can mostly make them by adding to the carbon chain of another fat & perhaps adding a double-bond or two.
So why are FAS levels elevated in PCa cells?
About 25 years ago, Alan Partin (Johns Hopkins) looked at "a relatively new marker, oncoantigen 519 (OA-519)" [1]. This was FAS:
"OA-519 staining of the primary prostate cancer was highly predictive in separating cases with organ-confined disease or capsular penetration versus cases with seminal vesicle invasion or lymph node metastases; Gleason score 6 or 7 was also predictive. In a logistic multivariate regression analysis, both OA-519 and Gleason score were strong independent predictors of pathologic stage ..."
If PCa, as it becomes more aggressive, turns to FAS for fatty acid synthesis, perhaps FAS is a good target?
In 2001, another team from Hopkins reported that [2]:
"Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensitive and androgen-independent prostate cancer."
"FAS expression ... was high in 82% of lethal tumors examined at autopsy."
"The re-emergence of FAS expression and activity during the development of androgen independence demonstrate that FAS may serve as a novel target for antimetabolite therapy in prostate cancer."
In 2003, a Finnish study [3] reported that:
"Fatty acid synthase (FAS) was found to be down-regulated by 1alpha,25(OH)(2)D(3)". i.e. by the hormonal form of vitamin D (aka: calcitriol, 1,25-D).
A 2003 study from Belgium [4] reported something similar for Epigallocatechin-3-gallate [EGCG], from green tea.
More importantly, perhaps, in a Mayo paper [5] from 2007:
"We have demonstrated that the 5 alpha-reductase inhibitor dutasteride, at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells."
In 2014, an Australian lab looked at Triclosan, a FASN inhibitor which was initially developed as a topical antibacterial agent [6]:
"These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer."
The consumption of food products containing high amounts of flavonoids has been reported to lower the risk of various cancers. The mechanisms underlying the cancer-protective effects of these naturally occurring polyphenolic compounds, however, remain elusive. Based on our previous finding that the cytotoxic effect of the flavanol epigallocatechin-3-gallate on prostate cancer cells correlates with its ability to inhibit fatty acid synthase (FAS, a key lipogenic enzyme overexpressed in many human cancers), we examined the anti-lipogenic effects of a panel of 18 naturally occurring polyphenolic compounds. In addition to epigallocatechin-3-gallate, five other flavonoids, more particularly luteolin, quercetin, kaempferol, apigenin, and taxifolin, also markedly inhibited cancer cell lipogenesis. Interestingly, in both prostate and breast cancer cells, a remarkable dose-response parallelism was observed between flavonoid-induced inhibition of fatty acid synthesis, inhibition of cell growth, and induction of apoptosis. In support for a role of fatty acid synthesis in these effects, the addition of exogenous palmitate, the end product of FAS, markedly suppressed the cytotoxic effects of flavonoids. Taken together, these findings indicate that the potential of flavonoids to induce apoptosis in cancer cells is strongly associated with their FAS inhibitory properties, thereby providing a new mechanism by which polyphenolic compounds may exert their cancer-preventive and antineoplastic effects.
Flavonoids constitute the largest and most important group of polyphenolic compounds in plants. They are widely distributed in many frequently consumed beverages and food products of plant origin such as fruit, vegetables, wine, tea, and cocoa (1, 2). The molecular structure of flavonoids consists of two aromatic rings (A ring and B ring), that are linked by a three-carbon bridge (Fig. 1). Depending on their oxidation state and functional groups, flavonoids are further divided in six subclasses: flavones, flavanones, flavanols, flavonols, isoflavones, and anthocyanidins.
Intake of beverages or food products containing flavonoids has been frequently associated with a reduced risk for developing various cancers (2, 4–6). Consumption of onions and/or apples, two major sources of the flavonol quercetin (1, 3), was inversely associated with the incidence of cancer of the prostate, lung, stomach, and breast (7–10). Frequent consumption of tea, an important source of both flavanols (1, 11) and flavonols (1), has been correlated with a lower incidence of cancer of the breast, prostate, bladder, lung, pancreas, colon, stomach, esophagus, and oral cavity (11–13). In addition, moderate wine drinkers also seem to have a lower risk to develop cancer of the lung, endometrium, esophagus, stomach, and colon (14–18). Besides anthocyanidins, red wine contains relatively high levels of both flavanols and flavonols (1, 19). Furthermore, also consumption of olives and/or olive oil, containing relatively large amounts of the flavones luteolin and apigenin, has been associated with a lower risk to develop cancer of the breast, ovary, and colon.
Although several molecules and pathways have been proposed as targets of flavonoids (3, 6), the precise mechanism by which these compounds exert their cancer-protective effects are poorly understood. Recently, we have shown that the flavanol EGCG,1 the main polyphenolic compound of green tea, inhibited fatty acid synthase (FAS) activity and lipogenesis in prostate cancer cells, an effect that was strongly associated with growth arrest and cell death (23). FAS is a key metabolic enzyme that catalyzes the synthesis of long chain fatty acids (24). In contrast to most normal tissues, which show low FAS expression, expression of FAS is markedly increased in various human cancers, including cancer of the prostate, breast, ovary, endometrium, colon, and lung (25–27). Up-regulation of FAS occurs early in tumor development and is further enhanced in more advanced tumors. In addition, high FAS expression levels often predict a poor outcome for cancer patients. We have previously demonstrated that RNA interference-mediated silencing of FAS severely inhibits lipogenesis and induces growth arrest and apoptosis in prostate cancer cells (28). Furthermore, blockage of FAS by the chemical inhibitors cerulenin and C75 also inhibits proliferation and is cytotoxic for various tumor cell lines in vitro and/or tumor xenografts in vivo (29–33). In the present work we have investigated whether, in addition to EGCG, other naturally occurring flavonoids also inhibit FAS activity and lipogenesis in cancer cells and whether this inhibition correlates with the effects of these polyphenolic compounds on cancer cell growth and survival.
....
DISCUSSION
Recently, we observed that the green tea polyphenol EGCG, the consumption of which correlates with a lower cancer risk, blocks FAS activity in prostate cancer cells. In the present work, we examined the anti-lipogenic effect of a panel of 18 polyphenolic compounds and showed that luteolin, quercetin, kaempferol, apigenin, and taxifolin also act as potent inhibitors of lipogenesis in intact prostate and breast cancer cells via blockage of the enzymatic activity of FAS. Interestingly, the anti-lipogenic effect of these compounds was strongly associated with their ability to arrest growth and induce apoptosis of prostate and breast cancer cells, indicating that FAS inhibition may be at least one of the mechanisms by which flavonoids exert their anti-carcinogenic effects.
Analysis of anti-lipogenic effects on intact cancer cells revealed that of 18 polyphenols, luteolin, quercetin, and kaempferol were the most potent inhibitors of lipogenesis followed by apigenin, taxifolin, and EGCG. At a concentration of 25 μM, no significant effects were observed for the other 12 polyphenols studied, although galangin, ECG, myricetin, and eriodictyol showed a trend to inhibit lipogenesis. In vitro assays on LNCaP cell extracts revealed that luteolin, quercetin, and kaempferol acted as inhibitors of enzymatic FAS activity and that the in vitro FAS inhibitory activity of these polyphenolic compounds paralleled their in vivo ability to block lipogenesis in prostate and breast cancer cells. These findings are in accordance with recently published data showing that several flavonoids (including luteolin, quercetin, and kaempferol) inhibit the activity of purified FAS, with a comparable order of inhibitory potencies luteolin > quercetin > kaempferol (40). Although we observed that EGCG acted as a more potent FAS inhibitor than luteolin, quercetin, and kaempferol in vitro, this stronger FAS inhibitory effect of EGCG was not reflected in vivo. Similarly, we observed that myricetin, which was demonstrated by Li and Tian to display a stronger FAS inhibitory activity than taxifolin in vitro (40), was a less potent inhibitor of lipogenesis than taxifolin in intact cells. Possible explanations for the observed differences between in vitro and in vivo data include differences in uptake, sequestration, and/or oxidation rate of flavonoids.
With regard to the structure-activity relationship of flavonoids, it can be noted that those flavonoids that significantly inhibit lipogenesis (luteolin, quercetin, kaempferol, apigenin, taxifolin, and EGCG) all contain hydroxyl groups on the 5 and 7 position of the A-ring, whereas flavone and 3-OH-flavone, which lack these 5,7-hydroxyls, do not affect lipogenesis. Furthermore, the four 5,7-hydroxyflavonols (myricetin, quercetin, kaempferol, and galangin) and the two 5,7-hydroxyflavones (luteolin and apigenin) studied, which inhibited lipid synthesis or at least showed a trend to inhibit lipogenesis, all contain a C-2,3 double bond and a 4-ketone function. In addition, within each flavonoid subclass, the 3′,4′-dihydroxyflavonoids (with 2 hydroxyls on the B ring) are most active (luteolin > apigenin; eriodictyol > naringenin; quercetin > kaempferol, galangin, and myricetin). Taken together, it can be concluded that the presence of a C-2,3 double bond, a 4-ketone function, and hydroxyl groups on positions 5, 7, 3′, and 4′ favor the potential of flavonoids to inhibit lipid synthesis in intact cells. Wang et al. (41) previously demonstrated that the presence of a galloyl moiety was essential for FAS inhibition by catechins: only EGCG and ECG (but not EC or EGC) inhibited FAS activity in vitro. In addition, they also observed that both EGCG and ECG showed irreversible slow binding activity, whereas other flavonoids (including quercetin and kaempferol) only showed reversible fast binding inhibition of FAS (41, 42), thereby suggesting that EGCG and ECG may inhibit lipogenesis by different mechanisms than other flavonoids.
At least six of the studied polyphenolic compounds (EGCG (23), luteolin, quercetin, kaempferol, apigenin, and taxifolin) have marked effects on cancer cell growth and survival. Several of our findings suggest that these effects are related to the ability of flavonoids to inhibit fatty acid synthesis. First, a comparative analysis of 18 naturally occurring flavonoids revealed that their ability to inhibit lipogenesis markedly correlated with their cytotoxic effects in cancer cells. Second, the dose-response curves of luteolin, quercetin, and kaempferol, reflecting the inhibition of total cancer cell lipogenesis as well as those reflecting the inhibition of phospholipid and triglyceride synthesis, show a striking parallelism with the dose-response curves reflecting the impact of these compounds on proliferation and viability of cancer cells. Several of these flavonoids also inhibit cholesterol synthesis, but this effect correlates less well with the effects on viability. For some compounds, such as galangin, marked inhibition of cholesterol synthesis (5-fold reduction) was observed at concentrations (12–25 μM) that did not affect phospholipid or triglyceride synthesis nor cell viability (data not shown). Third, specific blockage of FAS using RNA interference technology also resulted in growth arrest and cell death of cancer cells (28) and induced comparable morphological changes in LNCaP cells as observed after treatment with luteolin, quercetin, or kaempferol. Finally, the addition of exogenous palmitate, the most important end product of FAS activity, suppressed the cytotoxic effects of polyphenolic compounds, thereby providing evidence that FAS inhibition is a common denominator in the effects of these agents on cancer cells.
With respect to the potential use of luteolin, quercetin, and kaempferol as cancer-preventive or chemotherapeutic agents, it is worth mentioning that these compounds display very low toxicity in humans. Daily intake of relatively high doses of quercetin (1 g) or luteolin/apigenin (140 mg) for several weeks did not induce any side effects (43, 44). Moreover, the growth inhibitory and cytotoxic effects of these flavonoids may be relatively selective for malignant cells expressing high levels of FAS. In fact and again analogous to what we observed after selective inhibition of FAS by the use of RNAi (28), the proliferation rate and viability of nonmalignant fibroblasts expressing low levels of FAS was not affected by luteolin, quercetin or kaempferol and this despite a further lowering of lipogenesis in these cells. Whether this selectivity also applies in an in vivo situation requires further investigation.
The potential contribution of flavonoids to the cancer-preventive effects of polyphenol-rich diets of course depends on the daily intake and uptake of these compounds. The average flavonoid intake in the western world has been estimated at 1000 to 1100 mg per day (2, 3). However, it is obvious that significantly larger flavonoid portions can be taken up by individuals upon frequent consumption of particular flavonoid-rich food products. Several studies in humans have demonstrated that intake of food products containing quercetin or kaempferol results in plasma concentrations ranging from 0.6 to 6 μM (43, 45–49). In addition, the half-live of quercetin in humans is 20–30 h, suggesting that frequent consumption may result in accumulation of flavonoids in plasma and tissues (2), as previously observed for green tea polyphenols (50). Importantly, our data demonstrate that luteolin, quercetin, and kaempferol already inhibit FAS activity in cancer cells at relatively low concentrations (6–12 μM), which also induce significant cancer cell death. Thus, according to the pharmacokinetic studies discussed above and taking into account that different flavonoids may have additive effects and that regular intake may result in accumulation, flavonoid concentrations affecting FAS activity may be reached by the use of polyphenol-rich diets.
It should be mentioned that flavonoids may also contribute to cancer prevention by other mechanisms such as radical scavenging (2, 6), detoxification of mutagenic xenobiotics (6, 51, 52), and inhibition of topoisomerases (6, 53, 54), cyclin-dependent kinases (55, 56), and protein kinases (including phosphatidyl inositol 3-kinase) (57). The question may be asked as to whether some of these alternative effects of flavonoids could be secondary to inhibition of lipogenesis. Indeed, we have recently demonstrated that RNAi-mediated FAS inhibition in prostate cancer cells decreases the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains (58), membrane structures involved in signal transduction and cell migration (59). As a consequence, flavonoid-mediated inhibition of FAS activity in cancer cells may cause multiple downstream effects, resulting from disturbed membrane functions. Taken together, our findings show that flavonoids constitute interesting candidate molecules for cancer-preventive and/or antineoplastic therapies and that interference with endogenous lipogenesis may be an important mechanism underlying their effects.
I was reading up on Triclosan and found this on Wikipedia: Endocrine disruptor
Triclosan has been found to be a weak endocrine disruptor, though the relevance of this to humans is uncertain.[33][34] The compound has been found to bind with low affinity to both the androgen receptor and the estrogen receptor, where both agonistic and antagonistic responses have been observed.[33]
Luteolin, EGCG would appear to be better options. There does not appear to be a good supplement available for the former.
Much appreciated, Patrick. I have found two other possible sources of Luteolin. One supplier is Super Smart (amazon.com/Supersmart-MrSma... and the other is Axenic which sells in Canada but not the USA, which is odd (amazon.ca/100gm-Luteolin-98.... I suspect the latter is from China. What do you think?
I did further searching using the terms "Axeinc Australia" and found that it is registered in India (C1-702 BRAMHA SUN CITY WADGAONSHERI PUNE MH 411014 IN). The price is great but quality still remains dubious because of past history of drugs coming out of this country. Thanks for the assist. Cheers, Phil
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