5-LOX & Stemness.

[pjoshea13]

Prompted by a recent study [1]. {May be a bit heavy going for some. Apologies in advance.}

***

Between 1997 & 2002, while he was at UVA, Charlottesville, VA, Dr. Myers co-authored 5 PCa studies involving 5-LOX (5-lipoxygenase).

[2] 1997 "Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase."

[3] 1998 "Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells."

[4] 1999 "Lipoxygenase inhibition in prostate cancer."

[5] 1999 "Central role of arachidonate 5-lipoxygenase in the regulation of cell growth and apoptosis in human prostate cancer cells."

[6] 2002 "Molecular mechanisms of prostate cancer cell death triggered by inhibition of arachidonate 5-lipoxygenase: involvement of Fas death receptor-mediated signals."

***

Background.

Many here will know that some of the "healthy" oils that replaced "unhealthy" animal fat for cooking, have high levels of pro-inflammatory omega-6 fatty acid. Specifically linoleic acid [LA]. LA has an 18-carbon backbone, with double bonds at positions 9 & 12 (the carbon chain can bend at those points), to make it a polyunsaturated fatty acid. (The double bond at position 12 - six from the end - makes it an omega-6.)

The issue with LA is said to be that high levels can result in high levels of arachidonic acid [AA]. The body slaps a couple of carbons at the front of LA & adds two more double bonds at positions 5 & 8 to form AA. Lipid rafts in prostatic cells contain AA.

But the body will not create an unlimited amount of AA.

The real issue IMO is that the polyunsaturated fats create an unfavorable omega-3:6 ratio for most people & AA becomes over-represented in lipid rafts. [Corn oil is 52% LA]

When the body suffers viral or bacterial insult that could lead to significant cell death, nuclear factor kappaB [NF-kB] is activated. NF-kB causes scores of pro-survival proteins to be produced. Among them are the COX & LOX enzymes that will act on AA to produce inflammatory metabolites.

One of those enzymes - 5-lipoxygenase [5-LOX]:

"metabolizes arachidonic acid to 5-hydroperoxyicosatetraenoic acid (5-HPETE), which in turn is metabolized to various leukotrienes (i.e. leukotriene B4, leukotriene C4, leukotriene D4, and leukotriene E4 as well as to 5-hydroxyicosatetraenoic acid (5-HETE) which may then be further metabolized to 5-HETE's more potent 5-keto analog, 5-oxo-eicosatetraenoic acid (5-oxo-ETE)" [7]

This is all very well during a short-term illness, but PCa chronically activates NF-kB, & 5-HETE, etc, make the cancer more aggressive.

While NSAIDs target the COX enzymes, they are not effective against 5-LOX.

I have used 5-LOXIN for about a dozen years. It is derived from Boswellia serrata & has a high AKBA (Acetyl-11-keto-β-boswellic acid) content [8].

"... 5-LOXIN® is a selective, non-redox 5-LOX inhibitor, which means that its action is very targeted, not affecting other systems."

***

From the recent study:

"Acetyl-11-keto-β-boswellic acid {AKBA} suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties."

"Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC50 value in anti-proliferation was ∼17 μM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10-30 μM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/301...

[2] ncbi.nlm.nih.gov/pubmed/919...

[3] ncbi.nlm.nih.gov/pubmed/978...

[4] ncbi.nlm.nih.gov/pubmed/103...

[5] ncbi.nlm.nih.gov/pubmed/106...

[6] ncbi.nlm.nih.gov/pubmed/126...

[7] en.wikipedia.org/wiki/Arach...

[8] plthealth.com/products/5-loxin

[cesanon]

Patrick,

Can you help us synthesize this into behavioral / dietary changes?

I remember that Myers talked a fair bit about arachidonic acid.

1. He really really didn't like any corn products or any meat from animals (such a beef) which ate corn. But seemed to be good with sheep and goat cheese (as they will refuse to eat corn) and with lamb meat.

2. He really really didn't like canola (rapeseed) oil.

3. "The real issue IMO is that the polyunsaturated fats create an unfavorable omega-3:6 ratio for most people & AA becomes over-represented in lipid rafts. [Corn oil is 52% LA]" Any thoughts on how we can use this to inform our use of Omega supplements?

4. "While NSAIDs target the COX enzymes, they are not effective against 5-LOX.

I have used 5-LOXIN for about a dozen years. It is derived from Boswellia serrata & has a high AKBA (Acetyl-11-keto-β-boswellic acid) content [8]." Could you explain this a bit further and how it might inform what we do or not do, especially with aspirin?

5. Do you have any related practical tips?

[pjoshea13 in reply to cesanon]

1] Feed lots fatten beef. Unfortunately, the fat is higher in linoleic acid [LA]:

"Grass-fed tallow had ... 66 percent less omega-6 linoleic acid, and four times more omega-3 alpha-linolenic acid. The ratio of omega-6 to omega-3 fatty acids was over sixteen for the grain-fed tallow but only 1.4 for the grass-fed tallow." [A]

Myers was against alpha-linolenic acid [ALA], but balancing the omega-6:3 ratio would trump his concern about ALA, IMO.

2] Canola is only 19% [LA], but that can be significant for those who eat fried food.

It is 61% oleic acid.

Also, 9% ALA.

{Compare with olive oil: LA=10%, oleic=71%, ALA=<1%.}

Canola has a high smoke point & restaurants love it.

Canola comes from rape seed that has a lower level of antinutrients. Some think it is healthy because it has almost as much oleic acid as olive oil, plus the bonus of omega-3. But the omega-3 is ALA, which is associated with aggressive PCa.

3] I ate a can of sardines for breakfast yesterday. 2,500 mg of EPA/DHA. We use no cooking fat except olive oil & butter. I did use some butter during the day, but basically, my omega-3:6 ratio for the day was as good as it gets for me.

[4] Low-dose aspirin is not effective against COX enzymes in PCa cells that have activated NF-kB. Dose is too low.

Low-dose aspirin is strong enough to inhibit platelet aggregation & may therefore inhibit clot formation & metastasis.

Low-dose aspirin has no benefit against future cardiovascular events, except in those who have already suffered one.

None of the NSAIDs target 5-LOX. 5-LOXIN does.

5] Look in the USDA database to see what is in your cooking oil(s).

Try to figure out your daily omega-6:3 ratio. Should not by > 4:1 IMO.

-Patrick

[A] westonaprice.org/health-top...

[cesanon]

5-LOXIN

I am a bit confused about it? I did a search and Life extension seems to be selling something to inhibit it?

Life Extension 5-LOX Inhibitor with Apres Flex

amazon.com/Life-Extension-I...

Then again there is this? "Superior Labs Boswellia Extract - Pure NonGMO Boswellic 65% Acids w/Bioperine Superior Absorption Zero Synthetic Additives - Powerful Formula Joint, Knees, Hips, Migraine, Immune"

amazon.com/Superior-Labs-Bo...

And this? Vitacost Synergy 5-Loxin®-AKBA Boswellia Extract

amazon.com/Vitacost-Synergy...

[snoraste]

Patrick -

If our immune system needs 5-LOX to fight bacterial and viral infections, wouldn’t inhibiting it makes us susceptible to more frequent sickness?

[pjoshea13 in reply to snoraste]

Not susceptible - but, at the first sign of infection, it might be best to stop taking 5-LOXIN.

An effective NF-kB inhibitor will prevent 5-LOX production. NF-kB inhibits cell death. Nothing wrong with that unless one has cancer. Inhibiting NF-kB via polyphenols is a big part of my strategy, but I am concerned by the possibility that following a heart attack, there might be excessive cell death. On the other hand, when NF-kB is chronically activated, the resultant inflammation contributes to the risk of a heart attack.

-Patrick

[jdm3]

Aren't boswelia and frankincense the same thing?

[pjoshea13 in reply to jdm3]

I deliberately avoided making the Frankincense connection, since that is generally linked to Boswellia sacra rather than Boswellia serrata, & I don't know how the AKBA compares.

But, of course, the resin from five main Boswellia species has a long history of use.

-Patrick

[wagscure259]

If I might ask where do you acquire your 5 - Loxin ? Thank you

[wagscure259]

Thank you

[cujoe]

Patrick,

Thanks to you and Nalakrats I've been on 5-Lox supplements for the last year or so. Twice a day I usually take one each of the two flavors offered by Vitacost along with one Oregon Grape Extract. (with the expectation that there may be some positive synergy in the combination.)

I'm a 95+% vegan and look to get a favorable balance in omega 3 to 6. (much easier to do on WFPB diet.) I'm guessing you are already familiar with Wendy Demark-Wahnefried's flax/PCa research at Duke and later at MD Anderson.

WIth that in mind, what is your opinion of ground flax seed as a primary source of omega 3? It outstrips all other Omega 3 sources by a mile. Dr. Demark points out that it is a whole food, where as all oil derivatives are just that, i.e., derivatives. The positive results she got in her trials with PCa patients scheduled for RP surgery ran counter to the Hutch Meta study on fish oil that indicated a negative correlation. Maybe, whole PLANT food vs animal source had/has something to do with the contradiction??

Also what about Flax Seed Oil (ALA=7.5g, Lignand rich Flax=35mg, OA=2.2g, & LA=2g per tblsp) and Black Currant Oil (LA=360mg, GLA=136mg, ALA=104mg, & OA=88mg per 1000mg capsule).

As always, Thanks for all the time and effort you put in on our behalf.

Be Well - cujoe

[pjoshea13 in reply to cujoe]

Hi Cujoe,

I wrote about Wendy's studies 2 years ago:

healthunlocked.com/advanced....

Her 2012 paper is titled: "Prostatic Alpha-Linolenic Acid (ALA) Is Positively Associated with Aggressive Prostate Cancer ...". That brought her in line with Dr. Myers.

And, Alpha-Linolenic Acid [ALA] does not convert well to marine omega-3 [EPA/DHA], which is the target.

Fortunately for vegans, you can get EPA/DHA from the stuff the fish eat. Here is an example of an algal oil product:

swansonvitamins.com/source-...

Best, -Patrick

[cujoe in reply to pjoshea13]

Thanks, Patrick.

I guess by now I should already know to check your previous posts before asking a question?

Based on this Dr. Greger video,

nutritionfacts.org/video/sh...

I started taking the plant-based Ovega-3 supplement (similar to the Swanson) about two years ago - to keep my aging brain from shrinking any more. (At 71 years old, I guess it's current diminutive state explains my frequent childish behavior?)

I took one solftgel daily for about three months when I first started (along with my daily fat-soluble dose of C3 curcumin) and now do one about 3 days a week.

No doubt, it is now time to toss all my flax and chia products and go for some of Patrick's Famous Flax Hull Lignans.

Salute - cujoe

[pjoshea13 in reply to cujoe]

Hi Cujoe,

Thanks for the Greger link.

This is the first time I have come across a vegan site admitting that vegans might need a little supplemental help - & from Greger of all people!

Certainly a more helpful attitude than insisting that there are no deficiencies with the perfect vegan diet.

How does Greger deal with iodine deficiency? Many areas contain little or no iodine in the soil. Seaweed!:

youtube.com/watch?v=JOFvSaX...(Not working as expected?)

But how many vegans know that - or follow through?

etc.

-Patrick

[cujoe in reply to pjoshea13]

blimey,

I've been following Dr. Greger for years now, and find him to be pretty balanced. No doubt he does a bit of cherry-picking when it comes to nutritional research to support his WFPB point of view, but he seems always willing to revise a position based upon better information and newer research.

As my red blood counts have been trending down over time, I have added a low-dose non-heme iron supplement to see if I can boost it. The trend may be due to my first cancer, CLL, or to my non-meat diet. Once again Dr. Greger has addressed the iron issue for vegetarians/vegans with several of his short videos.

nutritionfacts.org/video/ri...

nutritionfacts.org/video/ar...

nutritionfacts.org/video/th...

You might also like this video about tumors and meat

nutritionfacts.org/video/ho...

If you have not spent much time at his website, I encourage you to do so. Type anything into the search bar and you will get a list of related videos. His four one-hour nutrition conference presentations are very good. (Do mind his cheesy humor and generous use of puns.)

Be Well - cujoe

[j-o-h-n]

bagels and lox... (cream cheese ala Nalakrats).... Sturgeon anyone?

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 12/12/2018 6:46 PM EST

[pjoshea13 in reply to j-o-h-n]

J-o-h-n,

What could be more logical than using lox to limit 5-LOX? Thanks.

-Patrick