Foods/Supplements-Vitamins: Arachidon... - Advanced Prostate...

Advanced Prostate Cancer

20,781 members25,884 posts

Foods/Supplements-Vitamins: Arachidonic acid [AA]

pjoshea13 profile image
1 Reply

So much for my alphabetic tour - I am back at the letter "A".

Arachidonic acid [AA] is an omega-6 fatty acid.

I have written a number of posts on inflammation over the years. Most of the chronic diseases, including cancer, are inflammatory in nature. Doctors tend to look at inflammation as a symptom of disease. Inflammation markers inversely correlate with survival. My view is that inflammation is a participant & can affect progression - and that it can be treated. Remove inflammation & the PSA doubling time may increase.

At the center of this is arachidonic acid. AA is created in the body from linoleic acid [LA]. LA has an 18-carbon chain & two double bonds at positions 9 & 12 - the latter is 6 from the end, making it an omega-6. With the synthesis of AA from LA, two carbons are added to the front to make a 20-carbon chain, & two new double bonds are introduced, but the last of the four double bonds is still 6 from the end, so AA is an omega-6 too.

AA is conditionally essential, in that, if there is insufficient dietary LA, there must be AA in the diet.

The body will not generally make more AA than it needs, but the diet may create a surplus. Is this dangerous? Not always:

"Some studies giving between 840 mg and 2,000 mg per day to healthy individuals for up to 50 days have shown no increases in inflammation or related metabolic activities.[32][33][34][35] However, others show that increased arachidonic acid levels are actually associated with reduced pro-inflammatory IL-6 and IL-1 levels and increased anti-inflammatory tumor necrosis factor-beta.[36] This may result in a reduction in systemic inflammation." [1]

The anti-AA gurus warn to limit egg intake because the yolks are high in AA. One source says 74 mg for a large egg, although that might be a bit low.

According to the USDA database, 100g "Chicken, broilers or fryers, dark meat, meat only, cooked, roasted" delivers 140 mg AA. 100g breast meat only has 8 mg.

100g "Beef, grass-fed, strip steaks, lean only, raw" has only 6 mg.

100g "Beef, chuck, under blade pot roast, boneless, separable lean only, trimmed to 0" fat, all grades, cooked, braised" has 63 mg.

100g "Fish, salmon, Atlantic, wild, raw" has 267 mg. That's a shocker!

whereas 100g cod has only 22 mg.

(100g = ~3.5 oz)

AA & PCa.

The lipid rafts of PCa cells accumulate AA. With marine omega-3 (EPA/DHA) in the diet, less AA will be present. i.e. there will be less inflammatory potential in the cell.

PCa cells chronically activate NF-kB (nuclear factor-kappaB). NF-kB, when activated, causes the transcription of many pro-survival proteins, including the enzymes responsible for the "arachidonic acid cascade" [1]:

"- The enzymes cyclooxygenase-1 and -2 (i.e. prostaglandin G/H synthase 1 and 2 {PTGS1 and PTGS2}) metabolize arachidonic acid to Prostaglandin G2 and prostaglandin H2, which in turn may be converted to various prostaglandins, to prostacyclin, to thromboxanes, and to the 17-carbon product of thromboxane metabolism of prostaglandin G2/H2, 12-Hydroxyheptadecatrienoic acid (12-HHT).[8][9]

"- The enzyme 5-lipoxygenase 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) (also see 5-Hydroxyicosatetraenoic acid.[10]

"- The enzymes 15-lipoxygenase-1 (ALOX15 and 15-lipoxygenase-2 (ALOX15B metabolize arachidonic acid to 15-hydroperoxyicosatetraemoic acid (15-HPETE) which may then be further metabolized to 15-hydroxyicosatetraenoic acid (15-HETE) and lipoxins;[11][12][13] 15-Lipoxygenase-1 may also further metabolize 15-HPETE to eoxins in a pathway analogous to (and presumably using the same enzymes as used in) the pathway which metabolizes 5-HPETE to leukotrienes.[14]

"- The enzyme 12-lipoxygenase (ALOX12) metabolizes arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE0 which may then be metabolized to 12-hydroxyeicosatetraenoic acid (12-HETE) and to hepoxilins.[15]"

STUDIES (oldest first):

[2a] (1997 - U.S.) This is from Dr Myers, when he was at UVA.

"Selective blockade of the different metabolic pathways of arachidonic acid (e.g. ibuprofen for cyclooxygenase, SKF-525A for cytochrome P-450, baicalein and BHPP for 12-lipoxygenase, AA861 and MK886 for 5-lipoxygenase, etc.) revealed that the growth stimulatory effect of arachidonic acid is inhibited by the 5-lipoxygenase specific inhibitors, AA861 and MK886, but not by others."

{Check out 5-LOXIN: [2b]}

"Addition of the eicosatetraenoid products of 5-lipoxygenase (5-HETEs) showed stimulation of prostate cancer cell growth similar to that of arachidonic acid, whereas the leukotrienes were ineffective."

"These experimental observations suggest that arachidonic acid needs to be metabolized through the 5-lipoxygenase pathway to produce 5-HETE series of eicosatetraenoids for its growth stimulatory effects on human prostate cancer cells."

Note that the same effect might occur with a NF-kB inhibitor.

Myers & Ghosh had another paper the next year, but I can't access the text [2c]:

"Arachidonic acid metabolism and cancer of the prostate."

[3] (2000 - U.S.)

This study is at odds with [2a] in that a COX inhibitor suppressed c-fos:

"c-fos is one of the earliest induced growth response genes ... In this study, expression of c-fos measured by semi-quantitative RT-PCR increased > 1.9-fold when prostate cancer cells were treated with AA in all experiments. The increased expression of c-fos may, at least in part, account for the increased PC-3 cell growth as previously observed (Tjandrawinata et al, 1997). Our results strongly suggest that AA induces c-fos expression through the biological activity of its product PGE for two reasons. First, PGE had a similar effect

on c-fos expression in PC-3 cells; and second, treatment with a cyclo-oxygenase inhibitor suppressed the induction of c-fos expression by AA."

[4] (2008 - Italy)

"Arachidonic acid modulates the crosstalk between prostate carcinoma and bone stromal cells."

"First, we observed that AA is a potent mitogenic factor for PCa cells through the production of both 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) metabolites."

"Several authors have previously demonstrated that tumor cells over-express AA metabolizing enzymes, and this feature may establish a bridge between the dietary fat intake and the progression of cancer. In particular, dietary n-6/n-3 fatty acid ratio seems to control not only the membrane fatty acid composition but also the growth of PCa xenografts in preclinical models"

"Our study and a plethora of data from other authors indicate that both LOX and COX pathways have to be considered important in the definition of AA-induced tumor aggressive behavior."

[5] (2008 - Japan)

"There is no argument that COX-2, LOX (especially, 5-LOX) PPAR-γ are involved in the initiation and promotion of PC tissues. It may be possible to use COX-2 and 5-LOX inhibitors, and PPAR-γ ligand as anticancer drugs for chemopreventive therapy in a single administration of a clinical dose."

[6] (2010 - Canada)

"De novo androgen synthesis and subsequent androgen receptor (AR) activation has recently been shown to contribute to castration-resistant prostate cancer (CRPC) progression. Herein we provide evidence that fatty acids (FA) can trigger androgen synthesis within steroid starved prostate cancer (CaP) tumor cells."

"In human CaP tissues the levels of proteins responsible for FA activation of steroid synthesis were observed to be altered during progression to CRPC. Further investigating this mechanism in LNCaP cells, we demonstrate that specific FA, arachidonic acid, is synthesized in an androgen-dependent and AR-mediated manner."

"We show that arachidonic acid induces androgen production in steroid starved LNCaP cells ..."

[7] (2012 - U.S.)

"Our results suggest that LOX metabolites such as 12-HETE are critical in prostate cancer progression and that the LOX pathway may be a target for treating and preventing prostate cancer."

...

COX-2 Inhibitors.

There have been three intervention studies using Celecoxib (celebrex), a selective COX-2 inhibitor:

[8] (2006 - U.S.)

"To assess the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in prostate-specific antigen (PSA) doubling time (PSADT) as the primary outcome variable."

"Participants had histologically confirmed prostate cancer, no recent hormone therapy, rising serum PSA after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases. Patients were randomly assigned to celecoxib (400 mg by mouth twice daily) or placebo. Treatment continued until disease progression or until adverse effects stopped treatment. A positive outcome was defined as post-treatment PSADT of more than 200% baseline PSADT with no new metastases."

"The study was terminated early after information about the cardiovascular safety of celecoxib prompted review of ongoing clinical studies."

However:

"Eight (20%) of 40 men in the placebo group and 15 (40%) of 38 men in the celecoxib group had post-treatment PSADT of more than 200% of baseline PSADT with no new metastases"

"Mean PSA velocity increased by 3.0% for the placebo group and decreased by 3.4% for the celecoxib group ..."

"Although the primary efficacy objective was not met, this study provides some evidence for biologic activity of celecoxib in prostate cancer. Compared with placebo, celecoxib significantly decreased mean PSA velocity and tended to increase the proportion of men who doubled their PSADT."

[9] (2009 - U.S. - Johns Hopkins)

"Patients with localized prostate cancer and Gleason sum > or = 7, prostate-specific antigen (PSA) > or = 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy."

"Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies."

[10] (2012 - International - the STAMPEDE study)

"Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A)."

"At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94"

"Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting."

...

I think this raises questions about aspirin studies. In my view, low-dose aspirin might be useful - not because it is a COX inhibitor - but because it it inhibits the aggregation of platelets, & may thus inhibit metastasis by preventing the formation of micro-clots.

The effect on platelets is achieved at the low dose, whereas that dose would not have much effect on COX-2. IMO

...

Omega-6 fatty acids get a bad press, but perhaps more than is deserved. When corn oil pushed out lard all those decades ago, we suddenly were using a fat that was 53.514% linoleic acid versus 10.200%. This must have been a really big deal to those with a significant intake of fat from cooking fat. It introduced a massive pro-inflammation element into the diet. The switch from animal (saturated) fat to vegetable (polyunsaturated) oils was a very large uncontrolled experiment.

But linoleic acid is an essential fatty acid.

It's main downstream product, arachidonic acid has been singled out because of the potential AA cascade of inflammatory products. But the core problem is that inflammatory diseases turn on that cascade via NF-kB activation. NF-kB is an ideal target IMO. There is a lot more to NF-kB than COX & LOX enzymes. Plant polyphenols are mostly NF-kB inhibitors. They have few if any side effects & can be taken at high doses.

What dose? The proof is in markers of inflammation: albumin, C-reactive protein, etc. Dose until happy & check on PSADT as the markers go down.

-Patrick

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

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

[2b] swansonvitamins.com/swanson...

[2c] ncbi.nlm.nih.gov/pubmed/943...

[3] ncbi.nlm.nih.gov/pmc/articl...

[4] erc.endocrinology-journals....

[5] ncbi.nlm.nih.gov/pmc/articl...

[6] ncbi.nlm.nih.gov/pubmed/197...

[7] ncbi.nlm.nih.gov/pmc/articl...

[8] jco.ascopubs.org/content/24...

[9] ncbi.nlm.nih.gov/pmc/articl...

[10] ncbi.nlm.nih.gov/pmc/articl...

Written by
pjoshea13 profile image
pjoshea13
To view profiles and participate in discussions please or .
Read more about...
1 Reply
Darryl profile image
DarrylPartner

Well done...very helpful!

You may also like...

Nuclear Factor-kappaB [NF-kB]

moratorium on cell death. Next there is the production of COX/LOX enzymes that act on arachidonic...

Foods/Supplements-Vitamins/Herbals

gamma oryzanol--and were evaluated for antitumor activity in severely immunodeficient mice bearing...

Calcium supplement with vitamin D

supplements? Does anyone know of any papers or studies pro or con about it? Is the suggestion...

Folic acid, Vitamin B12 and PCM.

folic acid 1 mg every daily and vitamin B12 1000 mcg every day. I have read that both folic acid...

Food supplements I hope will help

to select \\"healthy\\" supplements that may fight prostate cancer as well. I've included links to...