Folate - Folic Acid - Vitamin B9

[pjoshea13]

This post is prompted by an unexpectedly low test result this week:

2.2 ng/mL (ref: > 3.0)

Wik [1]i: "Folate deficiency is very rare in countries with folic acid fortification programs.", such as the U.S., which is why I have had no interest in testing. But I needed to get a B12 test & folate was included.

I'm happy enough having a low level, but do not know how that occurred.

Folate is the primary methyl donor in the body. It is of concern in PCa since cells avidly take up methyl and those cells tend to be hypermethylated. In particular, the promoter regions for tumor suppressor genes, which are never methylated in normal cells, are invariably methylated (silenced) in PCa cells.

The SAM cycle is:

... methionine ---> SAM ---> homocysteine + folate + B12 ---> methionine ...

Methionine is used to create SAM, the universal methyl donor in the body. The transfer of methyl to cells leaves homocysteine. If there is a sufficiency of folate & cofactors - particularly vitamin B12 - homocysteine will be recycled back to methionine. Otherwise, homocysteine levels will be on the high side (a good thing in some PCa survival studies.)

In wading through PubMed, I came across this curiosity (2020):

"Rise in serum folate after androgen deprivation associated with worse prostate cancer-specific survival"

"We documented testosterone and folate levels before and after ADT initiation ... Our primary outcome was overall mortality with secondary outcome of prostate cancer-specific mortality."

"We identified more rapid time to death from prostate cancer if folate levels increased to levels >200 ng/ml above their baseline ..."

The hypothesis was that (a) since fortification with folic acid began in 1998, folate levels have increases by a factor of 2.5, and (b) many men over age 60 also take a folic acid supplement, and (c) that with loss of testosterone, folate levels should increase. News to me.

Wiki [3]: "Folate is important for cells and tissues that divide rapidly. Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate drug methotrexate is often used to treat cancer because it inhibits the production of the active tetrahydrofolate (THF) from the inactive dihydrofolate (DHF)."

I have never heard of a PCa patient being treated with an antifolate drug. Anyone out there?

-Patrick

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

[2] pubmed.ncbi.nlm.nih.gov/324...

[3] en.wikipedia.org/wiki/Folat...

[timotur]

Interesting, related to vitamin B supplements, evidently the buildup of un-metabolized folic acid causes increased risk of cancer. Takeaway is to avoid foods fortified with B-vitamins._________________

Folic acid is a synthetic form of vitamin B9, also known as pteroylmonoglutamic acid.

It’s used in supplements and added to processed food products, such as flour and breakfast cereals.

Unlike folate, not all of the folic acid you consume is converted into the active form of vitamin B9 — 5-MTHF — in your digestive system. Instead, it needs to be converted in your liver or other tissues .

Yet, this process is slow and inefficient in some people. After taking a folic acid supplement, it takes time for your body to convert all of it to 5-MTHF.

Even a small dose, such as 200–400 mcg per day, may not be completely metabolized until the next dose is taken. This problem may become worse when fortified foods are eaten along with folic acid supplements .

As a result, unmetabolized folic acid is commonly detected in people’s bloodstreams, even in the fasted state.

High levels of unmetabolized folic acid have been associated with several health problems.

However, one study suggests that taking folic acid along with other B vitamins, particularly vitamin B6, makes the conversion more efficient.

Several studies indicate that chronically elevated levels of unmetabolized folic acid may have adverse health effects, including:

Increased cancer risk. High levels of unmetabolized folic acid have been associated with increased cancer risk. However, no evidence proves that unmetabolized folic acid plays a direct role .

Undetected B12 deficiency. Among elderly people, high folic acid levels can mask vitamin B12 deficiency. Untreated vitamin B12 deficiency may increase your risk of dementia and impair nerve function.

Even a small, daily dose of 400 mcg may cause unmetabolized folic acid to build up in your bloodstream.

healthline.com/nutrition/fo...

Also read:

academic.oup.com/ajcn/artic...

[Hailwood]

It was discovered that the delicious English delicacy Marmite could be used in folic acid deficiency anaemia, and as I consume Marmite in toast every day, my levels may increase, but I love Marmite, so what the hell.

[pjoshea13 in reply to Hailwood]

per 100g / per 8g / RDA

Thiamin (B1) 13.6 mg / 1.09 mg / 99%

Riboflavin (B2) 8.5 mg / 0.68 mg / 49%

Niacin (B3) 86 mg / 6.9 mg / 43%

Folic Acid (B9) 1500 µg / 120 µg / 60%

Vitamin B12 25 µg /2 µg [31] / 80%

[Hailwood in reply to pjoshea13]

Looks good to me

[CurrentSEO]

Not a good experience with methotrexate here pubmed.ncbi.nlm.nih.gov/236...

[bean1008]

I have read this thread a few times and I’m still confused whether I should be taking folic acid or not? It’s in my daily senior multivitamin (300 mcg Folic Acid). Should I be taking it or not?Thanks!

[Hidden in reply to bean1008]

I stopped all B Vitamin, including folic acid, supplements once I was diagnosed. I eat plenty of greens every day so I'm getting all the folate I need. I do believe folate is the better option. B-12 can be a problem as we age because we don't absorb it well...get a test and if you're low b-12, then start supplementing to raise it to good levels.

[pjoshea13 in reply to bean1008]

If you live in a country that adds folic acid to grains, & you eat bread & other baked goods (check the ingedients label) or rice, etc., you most likely do not need a supplement.

-Patrick

[bean1008]

Thanks, TomTom! I’ll look for a multi without the folic acid!

[LowT]

B vitamins important in neuro function. If on metformin need higher than low normal range of B12 levels. May contribute to incorrect dementia diagnosis if not addressed.

[MateoBeach]

Very complex topic. Thanks to Patrick for highlighting and clarifying it. I found the following review to resolve my questions. Convinced that those of us with APC should avoid folic acid / folate supplements and fortified foods.

ncbi.nlm.nih.gov/pmc/articl...

[GeorgeGlass in reply to MateoBeach]

Thanks Mateo. This is where the meat of the discussion is:

Prostate Carcinogenesis in vitro

There have been few studies looking into the effect of either folate deficiency or folate saturation on prostate carcinogenesis. Bistufli et al36 recently published the effects of relative folate deficiency on prostate cancer cell lines in vitro. When comparing prostate cancer cells in an environment with 100nM folic acid to one with a supraphysiologic level of 2μM folic acid, there was significant genetic and epigenetic instability as well as phenotypic changes seen in the cells grown in the lower concentration.36 More specifically, there were chromosomal rearrangements in 24–37% of cells and greater CpG island hypermethylation. Compared to the supraphysiologic control group, there were 14 new hypermethylated regions and altered global histone hypermethylation. They also reported significant increases in the dUTP:dTTP ratio, uracil misincorporation into DNA, and in the number of DNA single strand breaks.36

In order to examine the effect of physiologic levels of folate variation, Bistulfi et al37 investigated the effect of folate deficient, folate adequate, and high folate diets in the transgenic adenoma of the mouse prostate (TRAMP) model on prostate cancer tumorigenesis. The different diets did have a significant effect on serum and prostate tissue folate levels. Prostates in the folate deficient diet mice had a significantly lower cellular proliferation rate, as measured by Ki67 staining, compared to the normal and high folate diets.37 Additionally, the folate deficient mice had significantly fewer prostate lesions that progressed beyond HGPIN before 22 weeks (1/23), whereas the control and high folate diet groups had 10/22 and 7/21 mice that progressed to cancer (p=0.02), respectively. There were also significantly fewer mice that developed lymph node metastases in the folate deficient group compared to the control and high folate groups, while E-cadherin staining, which is generally lost during progression towards malignancy, was significantly retained in the folate deficient group compared to the two other groups.37 Therefore, while folate supplementation did not seem to enhance prostate cancer progression in this model, these findings do suggest that relative deficiency of folate blocks prostate tumorigenesis and progression to metastasis.

Another study performed by Petersen et al38 investigated the effect of common physiologic levels of folic acid on cultured human prostate cancer cell lines. The PC-3, LNCaP, and DU145 cell lines were exposed to 4nM, 20nM, or 100nM of folic acid. When compared to the U.S. population, these three levels of folic acid concentrations match well to folate deficiency, normal, and high serum folate, respectively. Both PC-3 and LNCaP cells showed significant increases in growth rates when they were grown in higher folate levels, however the DU145 cells did not show a difference.38 The same study also investigated the relative invasiveness of the cell lines between the folate groups; interestingly, a significantly greater proportion of cells in all three lines invaded across a matrigel matrix when grown in 100nM folic acid. These results suggest increased levels of folic acid are able to confer increased invasiveness, a measure of tumorigenicity, in prostate cancer cells.38

Prostate Cancer and Folate in vivo

Experimental models can reveal many novel discoveries; however the question remains as to whether the findings will translate to humans. Tomaszewski et al39 examined the relationship between patient serum folate levels and the proliferation rate of prostate tumor cells in Gleason Grade 7 radical prostatectomy specimens. When comparing tumors from the patients within the highest quintile of serum folate (117 +/− 15nM) to those from patients in the lowest quintile (18 +/− 9nM), tumors from the highest quintile group had an increased proliferative index, as measured by Ki67 staining, of 6.17 +/−3.2% vs 0.86 +/−0.92% (p<0.0001).39 Additionally, between both groups there was no significant difference in the proliferation index of the normal glands adjacent to tumor, which is likely reflective of their maintenance of normal cell cycle regulation. This study therefore supported the findings by Petersen et al,38 that increasing levels of serum folate lead to increased prostate cancer cell proliferation.

As reviewed by Mason et al,40 there was an increase in colorectal cancer incidence in both the U.S. and Canada that coincided with mandatory folic acid fortification in the mid 90’s. It has been postulated that the increased folate levels seen at this time may have allowed previously existing, however otherwise clinically indolent, tumors to proliferate. With the evidence just discussed regarding increasing tumorigenicity and proliferation rates of prostate cancer cells occurring in high folate environments,37–39 it is tantalizing to suggest the same phenomenon could explain the increase in prostate cancer incidence seen in North America from 1998–2002.1,3 In a recent case report, a patient with GS 3+4=7 prostate cancer had been managed successfully, PSA < 3ng/mL, for 10 years with intermittent androgen deprivation therapy using leuprolide, flutamide, and finasteride. He subsequently developed biochemical progression with a rising PSA to 21.3ng/mL, despite attempts at anti-androgen withdrawal, adding other anti-androgens, and eventually continuing leuprolide while adding docetaxel for over 18 weeks.41 It was then discovered that the patient had begun taking high dose supplements containing a total of 8mg of mixed folates and 5mg of Vitamin B12 (a folate coenzyme) at the beginning of his PSA rise. His serum folate at the time of his PSA peak was 303.6 nM. After stopping the supplementation and discontinuing his consumption of fortified foods, his serum folate level dropped to 9.06 nM. Remarkably, his PSA started to decline within two weeks, nadiring at 2.08 ng/mL.41

[GeorgeGlass]

Prostate Carcinogenesis in vitro

There have been few studies looking into the effect of either folate deficiency or folate saturation on prostate carcinogenesis. Bistufli et al36 recently published the effects of relative folate deficiency on prostate cancer cell lines in vitro. When comparing prostate cancer cells in an environment with 100nM folic acid to one with a supraphysiologic level of 2μM folic acid, there was significant genetic and epigenetic instability as well as phenotypic changes seen in the cells grown in the lower concentration.36 More specifically, there were chromosomal rearrangements in 24–37% of cells and greater CpG island hypermethylation. Compared to the supraphysiologic control group, there were 14 new hypermethylated regions and altered global histone hypermethylation. They also reported significant increases in the dUTP:dTTP ratio, uracil misincorporation into DNA, and in the number of DNA single strand breaks.36

In order to examine the effect of physiologic levels of folate variation, Bistulfi et al37 investigated the effect of folate deficient, folate adequate, and high folate diets in the transgenic adenoma of the mouse prostate (TRAMP) model on prostate cancer tumorigenesis. The different diets did have a significant effect on serum and prostate tissue folate levels. Prostates in the folate deficient diet mice had a significantly lower cellular proliferation rate, as measured by Ki67 staining, compared to the normal and high folate diets.37 Additionally, the folate deficient mice had significantly fewer prostate lesions that progressed beyond HGPIN before 22 weeks (1/23), whereas the control and high folate diet groups had 10/22 and 7/21 mice that progressed to cancer (p=0.02), respectively. There were also significantly fewer mice that developed lymph node metastases in the folate deficient group compared to the control and high folate groups, while E-cadherin staining, which is generally lost during progression towards malignancy, was significantly retained in the folate deficient group compared to the two other groups.37 Therefore, while folate supplementation did not seem to enhance prostate cancer progression in this model, these findings do suggest that relative deficiency of folate blocks prostate tumorigenesis and progression to metastasis.

Another study performed by Petersen et al38 investigated the effect of common physiologic levels of folic acid on cultured human prostate cancer cell lines. The PC-3, LNCaP, and DU145 cell lines were exposed to 4nM, 20nM, or 100nM of folic acid. When compared to the U.S. population, these three levels of folic acid concentrations match well to folate deficiency, normal, and high serum folate, respectively. Both PC-3 and LNCaP cells showed significant increases in growth rates when they were grown in higher folate levels, however the DU145 cells did not show a difference.38 The same study also investigated the relative invasiveness of the cell lines between the folate groups; interestingly, a significantly greater proportion of cells in all three lines invaded across a matrigel matrix when grown in 100nM folic acid. These results suggest increased levels of folic acid are able to confer increased invasiveness, a measure of tumorigenicity, in prostate cancer cells.38

Prostate Cancer and Folate in vivo

Experimental models can reveal many novel discoveries; however the question remains as to whether the findings will translate to humans. Tomaszewski et al39 examined the relationship between patient serum folate levels and the proliferation rate of prostate tumor cells in Gleason Grade 7 radical prostatectomy specimens. When comparing tumors from the patients within the highest quintile of serum folate (117 +/− 15nM) to those from patients in the lowest quintile (18 +/− 9nM), tumors from the highest quintile group had an increased proliferative index, as measured by Ki67 staining, of 6.17 +/−3.2% vs 0.86 +/−0.92% (p<0.0001).39 Additionally, between both groups there was no significant difference in the proliferation index of the normal glands adjacent to tumor, which is likely reflective of their maintenance of normal cell cycle regulation. This study therefore supported the findings by Petersen et al,38 that increasing levels of serum folate lead to increased prostate cancer cell proliferation.

As reviewed by Mason et al,40 there was an increase in colorectal cancer incidence in both the U.S. and Canada that coincided with mandatory folic acid fortification in the mid 90’s. It has been postulated that the increased folate levels seen at this time may have allowed previously existing, however otherwise clinically indolent, tumors to proliferate. With the evidence just discussed regarding increasing tumorigenicity and proliferation rates of prostate cancer cells occurring in high folate environments,37–39 it is tantalizing to suggest the same phenomenon could explain the increase in prostate cancer incidence seen in North America from 1998–2002.1,3 In a recent case report, a patient with GS 3+4=7 prostate cancer had been managed successfully, PSA < 3ng/mL, for 10 years with intermittent androgen deprivation therapy using leuprolide, flutamide, and finasteride. He subsequently developed biochemical progression with a rising PSA to 21.3ng/mL, despite attempts at anti-androgen withdrawal, adding other anti-androgens, and eventually continuing leuprolide while adding docetaxel for over 18 weeks.41 It was then discovered that the patient had begun taking high dose supplements containing a total of 8mg of mixed folates and 5mg of Vitamin B12 (a folate coenzyme) at the beginning of his PSA rise. His serum folate at the time of his PSA peak was 303.6 nM. After stopping the supplementation and discontinuing his consumption of fortified foods, his serum folate level dropped to 9.06 nM. Remarkably, his PSA started to decline within two weeks, nadiring at 2.08 ng/mL.41