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Foods/Supplements-Vitamins: Vitamin A (Retinol, Retinoic Acid [RA], Beta Carotene)

8 years ago•5 Replies

This is the first in a series of reviews of the PCa literature for foods & supplements. When I began looking at studies 12 years ago, I started with vitamin A, which I quickly discovered is not an easy topic.

It goes on a bit, so for those who want the bottom line: do not supplement with vitamin A (including cod liver oil) or beta carotene. IMO.

A. INTRODUCTION

A1. RETINOL.

Vitamin A is retinol. "When prepared as a dietary supplement, retinol is stabilized as the ester derivatives retinyl acetate or retinyl palmitate." [Wiki]

A2. RETINOIC ACID.

Retinoic acid is a metabolite of retinol, and is the form commonly used for most cell functions (but not all).

Drug forms with anticancer activity: 9-cis-retinoic acid, 13-cis-retinoic acid, all trans-retinoic acid [ATRA].

A3. BETA CAROTENE.

Beta carotene is the major pro-vitamin A carotene. It is selectively converted to retinol in the body, which means that it cannot cause hypervitaminosis A. i.e. the effect on retinol levels is limited.

A4. PROSTATIC RECEPTORS.

There are two types: RAR & RXR, but they each have three subtypes (alpha, beta & gamma). There are some sub-subtypes too - nothing is simple!

RARβ and RXRβ are both lost in PCa [B1d].

{"The retinoic acid receptor beta2 (RARβ2) is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, which has been shown to function as a tumor suppressor gene in different types of human tumors." [B4a]}

Why does PCa selectively suppress RAR? Either the alpha & gamma forms are irrelevant to PCa survival, or one or other is essential or beneficial.

"... findings indicate that RARalpha expression is correlated to some extent with tumor grade and its presence is more profound in highly proliferative tumors." [B4d]

"In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARγ-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma." [B4e] (Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells)

i.e. rather than using some form of vitamin A for therapy, we might be better off selectively inhibiting RARγ.

Seems that the deck might be stacked against vitamin A as a supplement.

A5. LRAT ENZYME.

The LRAT enzyme is involved with cellular uptake of vitamin A & the conversion to retinyl ester. LRAT appears to be lost in PCa [B1d].

B. STUDIES.

B1. RETINOL.

I have used serum studies [B1a,b,c,f,g,h,i] & plasma studies [B1e] in preferrence to diet questionaire studies. These studies, while generally indicative of a protective effect against PCa incidence, mostly do not address survival. Exception: [B1g].

{Serum - gold standard(?) - is the liquid after blood has been allowed to clot. Plasma is the liquid after blood has been prevented from clotting.}

Human tissue study [B1d] indicates that PCa alters the vitamin A environment substantially. Presumably, any protective effect has been lost.

Note that population studies may differ because circulating retinol levels may vary by country. e.g. Nordic countries consume higher amounts of cod liver oil for vitamins A&D, so preformed retinol in the diet might be higher. Thus, in one population, the lowest quintile might represent deficiency, whereas in another it might represent adequacy, while the upper quintiles might represent optimum & excessive levels, respectively.

The big outlier population study is the ATBC intervention trial on Finnish smokers. The aim was to lower lung cancer risk, but there were some alarming PCa findings. Vitamin A itself was not administered, but serum retinol was measured.

"In this largest study to date of vitamin A status and subsequent risk of prostate cancer, higher serum retinol was associated with elevated risk, with sustained high exposure conferring the greatest risk." [B1h]

The other outlier is the Prostate Cancer Prevention Trial, which looked at the placebo arm & found significant risk of PCa - including high-grade disease. [B1i]

[B1a] (1988 - Netherlands) strongly suggests that retinol is protective.

I have messed with Table 6, since the three middle serum quintiles have the same PCa risk. Being in the highest quintile reduces that risk by 46%, whereas being in the lowest quintile increases risk by 50%

The quintile ranges were defined by the control group (20% in each quintile). Only 11% of PCa cases made into the top quintile, while 33% were in the bottom quintile.

There is no indication as to supplement usage in the groups.

"The data ... suggest that serum retinol is protectively associated with all stages of the disease."

[B1b] (1990 - US, Maryland)

A bit different than [B1a]. The upper two quartiles had the same PCa risk. No advantage in being in the top quartile versus the third. Compared to these, the lowest quartile had a risk factor of 2.5; 1.67 for quartile two.

[B1c] (1999 - Switzerland)

"A slightly but nonsignificantly increased risk was observed for low levels of retinol."

[B1d] (2002 - US) Normal prostate cells metabolize retinol via the LRAT enzyme.

"... we analyzed LRAT protein expression in tissue sections from six prostatectomy specimens by immunohistochemistry. LRAT protein was predominantly expressed in the basal cells of normal prostatic epithelium, whereas its expression was lost in prostate cancer."

"RARβ and RXRβ {are} selectively lost in both prostate cancer and adjacent, morphologically normal prostatic tissue. In addition to the abnormally low levels of RARβ and RXRβ in prostate cancers, it was shown that in benign prostatic hyperplasia the concentration of retinol was 2-fold elevated, but in prostate carcinoma the level of RA was five to eight times lower than in normal prostate or in benign prostatic hyperplasia"

[B1e] (2007 - Europe - 137,000 men in 8 countries)

"We observed no associations between plasma concentrations of carotenoids, retinol, or tocopherols and overall prostate cancer risk."

[B1f] (2009 - US)

"Serum retinol concentrations were not associated with overall prostate cancer risk; however, the highest versus lowest concentrations of serum retinol were associated with a 42% reduction in aggressive prostate cancer risk .., with the strongest inverse association for high-grade disease (Gleason sum >7; odds ratio, 0.52 ...)."

[B1g] (2009 - US)

"serum retinol ... had no apparent effect on survival."

[B1h] (2011 - Finland-US)

"Greater exposure to retinol (vitamin A) may prevent prostate cancer, although under some conditions it could promote cell growth and de-differentiation."

"We observed a positive relation between retinol concentrations and subsequent risk of both total and aggressive prostate cancer, with a 20% greater overall risk for men in the highest retinol quintile."

"The biologic mechanism through which higher circulating retinol might increase the risk of prostate cancer is unknown and will require further basic or clinical study."

Note that:

- men did not receive additional vitamin A in this study

- Finns, via cod liver oil, might have higher levels of retinol than other countries as a whole

- the men were smokers

- Finland is not known for over-screening

[B1i] (2015 - US)

"Serum retinol concentrations were associated with {a 30%} increased risk of total prostate cancer ... comparing the highest quartile of serum retinol with the lowest ... and {a 74% increased risk of} high-grade prostate cancer ... in the placebo arm of the trial only."

"No associations were observed for retinol ... in the finasteride arm." Isn't that odd?

B2. RETINOIC ACID.

[B2a] (1999 - France)

A Phase II clinical trial of all-trans retinoic acid [ATRA] in CRPC cases.

"All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Toxicity was mild. No patient stopped therapy because of toxicity. Of the patients 4 (15%) demonstrated a biological response of 50% or greater serum prostate specific antigen decrease. No objective response was observed among 11 patients with measurable metastases."

"All-trans retinoic acid has minimal activity in hormone refractory prostate cancer."

[B2b] (1997 - US)

Another Phase II clinical trial of all-trans retinoic acid [ATRA] in CRPC cases.

"We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment."

Other trials, not considered because retinoic acid was not used as monotherapy:

[B2c] (1999 - US - Phase I) 13-cis-retinoic acid, interferon alfa, and paclitaxel

[B2d] (2003 - US - Phase I) 13- cis-retinoic acid, paclitaxel and interferon alpha

[B2e] (2010 US - Phase II) mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel

B3. BETA CAROTENE.

B3-ATBC. The Alpha-Tocopherol, Beta-Carotene [ATBC] Cancer Prevention Study.

"29,133 male smokers aged 50-69 years from southwestern Finland were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5-8 years"

Of the intervention arms, beta carotene (only) increased risk, while alpha tocopherol (only) decreased risk. As one might expect, the two together were neutral.

[B3-ATBC-a] (1995 - Finland/US)

"beta-Carotene treatment did not result in a decrease in cancer at any of the major sites but rather in an increase at several sites, most notably lung, prostate, and stomach (number of cases 474 compared with 402, 138 compared with 112, and 70 compared with 56, respectively). "

[B3-ATBC-b] (1998 - Finland)

"Among subjects receiving beta-carotene (n = 14560), prostate cancer incidence was 23% higher ... and mortality was 15% higher ... compared with those not receiving it"

[B3-ATBC-c] (2009 - Finalnd/US)

"Serum β-carotene ... and supplemental β-carotene had no apparent effects on survival."

However "those with fatal prostate cancer were slightly more likely to have been assigned to the β-carotene only group."

[B3-ATBC-d] (2014 - Finland) 18-year postintervention follow-up

"α-Tocopherol decreased post-trial prostate cancer mortality {by 16%}, whereas β-carotene increased it {by 20%}."

B3-CARET The Carotene and Retinol Efficacy Trial (CARET).

"CARET was a multicenter randomized, double-blind, placebo-controlled chemoprevention trial testing whether daily supplementation with 30 mg β-carotene + 25,000 IU retinyl palmitate would reduce lung cancer risk among 18,314 heavy smokers, former heavy smokers, and asbestos-exposed workers. The intervention ended 21 mo early in January 1996 when interim analysis found evidence that the supplements increased the risk of lung cancer and total mortality in this high-risk population by 28% and 17%, respectively."

Unlike the ATBC trial, there were only two arms, which explains why a null effect was seen (unless additional supplements were used).

[B3-CARET-a] (2009 - US)

"Neither the CARET nor other supplements were associated with total prostate cancer risk."

"For aggressive prostate cancer, men in the CARET intervention arm who used additional supplements had a relative risk for aggressive prostate cancer (Gleason >or=7 or stage III/IV) of 1.52"

B3-KIHD The Kuopio Ischaemic Heart Disease Risk Factor (KIHD) cohort

997 middle-aged Finnish men

[B-KIHD-a] (2012 - Finland)

"After adjusting for age, examination yr, family history of cancer, BMI, pack-yr of smoking, alcohol consumption, education, physical activity, serum total cholesterol, and serum α-linolenic acid, men in the highest tertile of serum concentrations of β-carotene had 2.3-fold higher risk of prostate cancer as compared to those in the lowest tertile ..."

B3-PLCO The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

[B3-PLCO-a] (2006 - US)

"Supplemental beta-carotene intake at a dose level of at least 2000 microg/day was associated with decreased prostate cancer risk in men with low (below the median of 4129 microg/day) dietary beta-carotene intake" Risk cut in half.

The benefit of supplementation was seen in men who had low intakes from food.

B4. PROSTATIC RECEPTORS.

[B4a] (2013 - China)

This is a meta-study. Methylation is a common cause of gene silencing. It is an epigenetic change that can theoretically be reversed. The analysis found that RARβ2 methylation was 17.62 times more likely in PCa cases.

"The detection of RARβ2 methylation in urine or serum is a potential non-invasive diagnostic tool in prostate cancer."

[B4b] (2013 - Iran)

"Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis were positive for RARB methylation"

[B4c] (2012 - Romania)

"Promoter hypermethylation of RARβ2 gene was detected in serum samples from 89 of 91 (92.86%) patients with PCa, and in 10 of the 94 (10.7%) patients with BPH."

[B4d] (2000 - Greece)

"RARalpha positivity was detected in all cases of prostatic carcinoma, with a more profound expression in well differentiated cancers. A statistically significant correlation between RARalpha staining and tumor grade was found ..."

[B4e] (2001 - UK)

"results suggest that antagonism of RARγ is sufficient to compromise survival and growth, at least of PC-3 and DU145 cells."

-Patrick

[B1a] (onlinelibrary.wiley.com/sto...

[B1b] ncbi.nlm.nih.gov/pubmed/234...

[B1c] ncbi.nlm.nih.gov/pubmed/100...

[B1d] cancerres.aacrjournals.org/...

[B1e] ajcn.nutrition.org/content/...

[B1f] cebp.aacrjournals.org/conte...

[B1g] ncbi.nlm.nih.gov/pubmed/193...

[B1h] aje.oxfordjournals.org/cont...

[B1i] ncbi.nlm.nih.gov/pubmed/262...