Inhibition Of PUFA Metabolism (LOX) Trigger Immediate Apoptosis In Prostate Cancer

[haidut]

These studies show that PUFA has both direct (linoleic) and secondary (through LOX) stimulating effect on prostate cancer growth, independently of any hormones. Inhibiting the LOX-5 pathway led to immediate growth arrest and apoptosis of prostate cancer cells.
The important message for both forum users and the medical fraudsters is that PUFA and its metabolic pathways are required for prostate cancer progression/development and hormones like DHT do not play any bad role given other studies I posted on PUFA inhibiting androgen synthesis and androgen receptor expression. Perhaps even more importantly, addition of the amino acid NAC blocked the apopotosis and restored cancer growth.

Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. - PubMed - NCBI
"...Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer."

Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. - PubMed - NCBI
"...Dietary fatty acids (FAs) may be involved in the carcinogenic process within the prostate gland and progression to clinically manifest disease. We have shown that growth of the androgen-unresponsive PC-3 human prostate cancer cell line is stimulated in vitro by the presence of linoleic acid (LA), an omega-6 polyunsaturated FA. The response was positively related to the FA concentration over the entire range examined (5-750 ng/ml). Conversely, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two omega-3 FAs present in fish oils, inhibited PC-3 cell growth in a dose-dependent manner; both were equally effective, with an approximately 65% reduction in growth occurring at a concentration of 2.0 micrograms/ml (P less than 0.001). The DU 145 human prostate cancer cell line, which is also androgen-unresponsive, showed no growth response to LA and was less susceptible to growth inhibition when cultured in the presence of omega-3 FAs. Growth experiments with indomethacin, esculetin, and piroxicam, pharmacological inhibitors of eicosanoid biosynthesis with differing sites of action, indicated that human prostate cancer cell growth requires intact metabolic pathways for both leukotriene and prostaglandin production."

 

[Wagner83]

These studies are 20-30 years old too..

This made me laugh:
Linoleic acid - Wikipedia
"Along with oleic acid, linoleic acid is released by cockroaches upon death which has the effect of preventing other roaches from entering the area. This is similar to the mechanism found in ants and bees, which also release oleic acid upon death.[8]"

 

[haidut]

These studies are 20-30 years old too..

This made me laugh:
Linoleic acid - Wikipedia
"Along with oleic acid, linoleic acid is released by cockroaches upon death which has the effect of preventing other roaches from entering the area. This is similar to the mechanism found in ants and bees, which also release oleic acid upon death.[8]"

I know, right. And we, smart humans, ingest the stuff that other animals use to signal death. Maybe humans should get the Darwin Award as species.

 

[nullredvector]

i think boswellia inhibits LOX. anything else?

edit: wiki:

Examples of 5-LOX inhibitors include drugs, such as meclofenamate sodium[3] and zileuton.[3][4]

Some chemicals found in trace amounts in food, as well as some dietary supplements, have been shown to inhibit 5-LOX; these include baicalein,[3] caffeic acid,[3] curcumin,[3] hyperforin[5][6][7] and St John's wort.[5][6][7

still not great

 

[DennisX]

Life Extension has a 5-Lox inhibitor called 5-Lox Inhibitor

 

[haidut]

Life Extension has a 5-Lox inhibitor called 5-Lox Inhibitor

Vitamin E, minocycline, and I think ketotifen are all LOX inhibitors. Aspirin is also a LOX inhibitor but it was 12/15-LOX that was confirmed. Not sure if it is LOX-5 as well.

 

[tca300]

@haidut Are you aware of how much Vitamin E Ray has reccomended for protection from stored PUFA? I can't find anything. Thanks!

 

[haidut]

@haidut Are you aware of how much Vitamin E Ray has reccomended for protection from stored PUFA? I can't find anything. Thanks!

His recommendations have somewhat changed, depending on his diet. I think he says that for most people even 400 IU weekly would be enough, and for people who have low PUFA stores, even 200 IU weekly would be enough. He has said a few times he takes 200 IU weekly on his skin.

 

[Mito]

His recommendations have somewhat changed, depending on his diet. I think he says that for most people even 400 IU weekly would be enough, and for people who have low PUFA stores, even 200 IU weekly would be enough. He has said a few times he takes 200 IU weekly on his skin.

Do you think the 0.4 mg alpha-tocopherol per gram of PUFA is a good rough guideline for dietary PUFA?

 

[haidut]

Do you think the 0.4 mg alpha-tocopherol per gram of PUFA is a good rough guideline for dietary PUFA?
View attachment 4771

I posted a study long time ago saying due to high unsaturation of some of the fats we eat, 1mg - 2mg per gram of PUFA may be needed, if the PUFA is consumed every day. For people eating mostly cold-water fish (in some cultures) 2mg per gram of PUFA is probably best. For the rest of us, 1mg per gram is probably enough. The 0.4mg per gram may be too low as the study showed since increasing it to 1mg/g lower incidence of heart disease.

 

[Xisca]

curcumin

Yes, I also sent some to my mother, it is often mentionned against cancer.
And anti-inflamatory...

 

[gilson dantas]

Very good @haidut!

 

[Base Ball]

I've talked to a lot of oncologists over the past couple years about prostate cancer, and have yet to run into one that wants to inhibit the Lox-5 pathway, much less have a conversation about it. The fact that piece of information has been around for 20 years should give you an idea of what isn't being taught in med school. Instead they are learning about the virtues of abiraterone and prednisone.

 

[tca300]

@haidut Do you know much about the prostaglandins produced by PUFA that we can make ourselves? ( from mead acid for example ).
Do you think those prostaglandins could stimulate cancer growth too? Thank you!

 

[haidut]

@haidut Do you know much about the prostaglandins produced by PUFA that we can make ourselves? ( from mead acid for example ).
Do you think those prostaglandins could stimulate cancer growth too? Thank you!

I think unlike arachidonic acid, Mead acid is an inhibitor of COX and LOX so even if it serves as a precursor to postaglandins and leukotrienes it would be very small effect.

 

[gilson dantas]

I've talked to a lot of oncologists over the past couple years about prostate cancer, and have yet to run into one that wants to inhibit the Lox-5 pathway, much less have a conversation about it. The fact that piece of information has been around for 20 years should give you an idea of what isn't being taught in med school. Instead they are learning about the virtues of abiraterone and prednisone.

My friend, all the urologists and oncologists I saw here, at my country, were very weak, they never said nothing about the origin of prostate tumor; they still speaking against testosterone and DHT; they do not know NOTHING about a diet pro-thyroid; and also they still doing [against our health] carcinogenics exams, byopsies that spread cancer, and chemo and radiation, irrational "treatments" that kill people or people´s quality of life etc...

 

[Mito]

@haidut Are you aware of how much Vitamin E Ray has reccomended for protection from stored PUFA? I can't find anything. Thanks!

His recommendations have somewhat changed, depending on his diet. I think he says that for most people even 400 IU weekly would be enough, and for people who have low PUFA stores, even 200 IU weekly would be enough. He has said a few times he takes 200 IU weekly on his skin.

Not specific to PUFA protection but comment on Vitamin E dose nevertheless.

From Iron's Dangers.

Q. I can't avoid all those foods, especially the bread and grains. What can I do to keep the iron I ingest from harming me?

Iron destroys vitamin E, so vitamin E should be taken as a supplement. It shouldn't be taken at the same time as the iron-contaminated food, because iron reacts with it in the stomach. About 100 mg. per day is adequate, though our requirement increases with age, as our tissue iron stores increase. Coffee, when taken with food, strongly inhibits the absorption of iron, so I always try to drink coffee with meat. Decreasing your consumption of unsaturated fats makes the iron less harmful. Vitamin C stimulates the absorption of iron, so it might be a good idea to avoid drinking orange juice at the same meal with iron-rich foods. A deficiency of copper causes our tissues to retain an excess of iron, so foods such as shrimp and oysters which contain abundant copper should be used regularly.

 

[haidut]

Not specific to PUFA protection but comment on Vitamin E dose nevertheless.

From Iron's Dangers.

Q. I can't avoid all those foods, especially the bread and grains. What can I do to keep the iron I ingest from harming me?

Iron destroys vitamin E, so vitamin E should be taken as a supplement. It shouldn't be taken at the same time as the iron-contaminated food, because iron reacts with it in the stomach. About 100 mg. per day is adequate, though our requirement increases with age, as our tissue iron stores increase. Coffee, when taken with food, strongly inhibits the absorption of iron, so I always try to drink coffee with meat. Decreasing your consumption of unsaturated fats makes the iron less harmful. Vitamin C stimulates the absorption of iron, so it might be a good idea to avoid drinking orange juice at the same meal with iron-rich foods. A deficiency of copper causes our tissues to retain an excess of iron, so foods such as shrimp and oysters which contain abundant copper should be used regularly.

Yes, thanks. The 100mg is about 150 IU so close to the 200 IU I have seen him mention in other places.

 

[Sativa]

COX & LOX inhibitors are ideal!
It means increased level of endocannabinoids...

Since both exogenous & endogenous pufa's are metabolized into notable cannabinoids, that means the endocannabinoid system is definitely an area of relevant interest, and ensuring it's functioning coherently. Obviously, this:

Cannabinoid CB1 Receptors are localized in Mitochondria and regulate mitochondrial respiration.
The CB1 receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism.​

aside - If you added some MAGL/FAAH inhibition, you'd improve the benefits, as shown below:

The accompanying graphic:

The eCB system is a homeostatic mechanism; involving-
(1) the endogenous lipid transmitters: endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG)
...
eCBs refer to the wide spectrum of lipid-derived fatty acid structural analogues, AEA & 2-AG are the best described (Fig. 1).
These naturally occurring cannabinoids present similar psychoactive properties to THC. They act on both receptors CB1R and CB2R.
There is an increasing interest into eCB-like molecules that converge on common catabolic and metabolic pathways, notably non-cannabinoid AEA structural analogues, palmitoylethanolamine & oleoylethanolamine​