Do Antioxidants Prevent or Accelerate Cancer?

In a recent article published in Medscape, the authors state that antioxidants are not only useless in preventing cancer, but quite possibly promote cancer growth. The target audience for this article is primary care clinicians, oncologists, nurses, and other clinicians who care for patients at risk for cancer, with the purported goal of providing “medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.”

I find this article disturbing, to say the least. Here’s why:

1) The article is blatantly biased. The authors point out only the few studies that have concluded negative results, while totally ignoring all of the positive studies—of which there are several hundred, or more. I do not understand how in good conscience they can skew the research findings in this way. Furthermore, I’m not certain of what they have to gain from this inaccurate representation of the total body of research available.

2) Their theory of antioxidants in relationship to cancer is completely wrong. The studies they use for their findings involve mostly synthetic forms of vitamin or mineral isolates. This is far removed from nature, and something I would never recommend. It’s essential to understand that the negative impact and possible increase in cancer incidence is related to a substance being a ‘PRO-OXIDANT’ and not an anti-oxidant. For example, high doses of vitamin C, K-3, beta-carotene, and E are all pro-oxidative when used as isolates, in high doses, and in certain conditions. It’s well established that smokers who take synthetic beta-carotene have an increased incidence of lung cancer. This does not mean that antioxidants cause cancer.

3) Details matter! It raises my ire when people use the word antioxidant in a general way. What specifically are they talking about? For example, the researchers for this article refer to the SELECT trial. Let’s explore this in a bit more depth to understand what the trial really reveals about antioxidants.

 

Understanding The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

In the 1980’s and 1990’s, a number of studies suggested that supplementing with vitamin E and selenium provided protection against prostate cancer. Thus, in 2001, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) began with 36,000 healthy, middle-aged volunteers. The men were divided into four groups, with each man given two pills each day: 400 international units (IU) of vitamin E plus 200 micrograms of selenium; vitamin E plus a placebo; selenium plus a placebo; or two placebos.

Although SELECT was intended to last until 2011, it was stopped three years early because neither vitamin E nor selenium were demonstrating benefit—and there were some indications that the supplements might actually be causing harm. In this widely publicized trial, researchers reported that there was no protective effect from selenium and suggested that vitamin E increased prostate cancer risk.

The effects of the supplements differed substantially between men with low levels of the nutrients at baseline and those with high levels.

1) Selenium supplementation increased the risk of prostate cancer in men who started the study with high selenium levels, but not in those with low selenium levels.

2) Vitamin E alone increased prostate cancer risk, but only in those men who began the study with low selenium levels.

3) Specifically, in the men with low levels of selenium randomized to receive vitamin E alone, the total risk for prostate cancer increased by 63% (P = .02) and the risk for high-grade cancer increased by 111% ( P = .01)

This might explain why, in the 2008 SELECT results, only the men randomized to receive vitamin E alone—not those who received both vitamin E and selenium—had an increased risk for prostate cancer. Selenium might protect men from the harmful effects of vitamin E. So selenium, at low levels, is not necessarily harmful to men.¹

What was not taken into consideration was the form of the supplements, and this is significant. In the SELECT study, selenium (200 μg/day from L-selenomethionine) and vitamin E (400 IU/day of all-rac-α-tocopheryl acetate) were used.

Although selenomethionine is one of the natural forms of selenium, it is an isolate and differs from selenium yeast. Selenium yeast is the most effective and safest form of selenium. However, every other study on selenomethionine has been positive as well. It is only the DL form of selenomethionine and sodium selenite that I avoid using because of the mixed results in data and because they are not natural forms of the mineral.

Selenium yeast is produced when selenium is naturally incorporated into the protein of growing yeast under optimal conditions. The result is yeast with a high concentration of the selenium-containing proteins selenomethionine (the form found in Brazil nuts) and selenocysteine. I suspect that the main problem in the SELECT study was the form of vitamin E used (all-rac-α-tocopheryl acetate), which again, is synthetic and an isolate, and thus very different from natural vitamin E. A synthetic isolate does not mimic natural vitamin E. It isn’t E-complex and it isn’t the tocotrienol form, which are now believed to be the most active disease preventive nutrients in the vitamin E family.

Many Studies Find Selenium Protects Against Cancer

I find it curious that the SELECT trial has garnered so much attention, without any mention of the hundreds of other trials involving selenium and E. For example, in a study published in 2004 in the Journal of the National Cancer Institute, researchers evaluated serum selenium levels and prostate cancer risk in the Physicians’ Health Study. They found an inverse association between baseline plasma selenium levels and the risk of advanced prostate cancer, which suggests that higher levels of selenium may slow prostate cancer progression.²

Study after study shows a connection between selenium and prostate cancer. In the now famous Clark Study, a 63% reduction in prostate cancer was found in men who received 200 micrograms of selenium from selenium-enriched yeast containing mostly selenomethionine.³Another study conducted at Stanford University found that low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer.⁴ German researchers have also concluded that decreased selenoprotein concentration in serum appears to represent an additional valuable marker for diagnosing prostate cancer.⁵

Both case-control and randomized placebo-controlled trials in humans suggest that selenium can decrease the risk of developing prostate cancer. In addition, many epidemiologic observations support selenium as a protective agent against cancer.⁶

The strongest evidence for the protective effect of selenium comes from the Nutritional Prevention of Cancer Trial. In this study, 1,312 participants took the equivalent of 200 µg yeast per day vs placebo. After 4.5 years the incidence of prostate cancer was reduced in those taking selenium by two-thirds compared to the placebo group. Reanalysis of the effect of selenium supplementation with a mean follow up of 7.5 years continues to show a marked reduction of the incidence of prostate cancer, with the strongest effect for those who entered the study with a PSA <4 ng/ml and the lowest serum levels of selenium.⁷

Theories Of How Selenium May Protect Against Cancer

Selenium inhibits tumorigenesis in a variety of experimental models, and a number of potential mechanisms have been proposed for its antitumorigenic effects. Accumulating evidence suggests that it works by inhibiting important early steps in carcinogenesis by inhibition of cellular proliferation, induction of apoptosis, and modulation of androgen-regulated genes.^8,9,10

Lab studies also show that selenium inhibits prostate cancer angiogenesis and metastases. An animal study found that inorganic selenium (sodium selenate) significantly retarded the growth of primary prostatic tumors and the development of retroperitoneal lymph node metastases, which was associated with a decrease in angiogenesis.¹¹ Another lab study found that oral selenium resulted in lower levels of DNA damage in prostatic epithelial cells and increased intraprostatic apoptosis.¹²

Of course, it’s important to know that selenium levels can be effectively increased in prostate tissue. In a clinical trial comparing 200 µg oral selenium per day with placebo in 51 men who underwent transurethral resection of the prostate for benign prostatic hyperplasia and who had normal pretreatment serum levels of selenium, selenium supplementation resulted in significantly higher levels of selenium in prostatic tissue.¹³ Together, these two studies demonstrate that orally ingested selenium reaches the prostate gland and modulates markers of oxidative stress relevant to the proposed molecular mechanisms of its protective effects.

Another way that selenium exerts protective effects may be through its interaction with cadmium, a toxic and suspected carcinogenic element found in many foods, in drinking water, and in the environment. Cadmium is considered a significant prostate cancer risk factor because it stimulates the growth of prostate epithelial cells and promotes their malignant transformation. The excessive accumulation of cadmium in the prostates of smokers along with sub-optimal selenium intakes could explain why smokers develop more aggressive and lethal forms of prostate cancer than nonsmokers.¹⁴

Combinations of Nutrients Provide Superior Protection

Numerous studies indicate that a combination of antioxidant nutrients provides better protection against cancer than relying on a single nutrient. Both endogenous and exogenous antioxidants have been shown to play an important and interdependent role in preventing clinically significant prostate cancer.¹⁵

For example, research demonstrates that greater levels of selenium, vitamin E, and lycopene reduce prostate cancer risk in one out of every four Caucasian males and those who inherit a specific genetic variation that is particularly sensitive to oxidative stress.¹⁶ And a recent study found that higher prediagnostic serum concentrations of alpha tocopherol (vitamin E) is associated with a lower risk of developing prostate cancer, particularly advanced prostate cancer.¹⁷

Another study found that levels of vitamin A, C, and E, selenium, and zinc were significantly lower in patients with prostate cancer. At the same time, copper levels and malondialdehyde (a lipid peroxidation marker) were significantly higher in patients with prostate cancer compared to controls.¹⁸

Numerous studies support the use of vitamin E for prostate health. The benefits, however, are directly related to the form that is used. Alpha-tocopheryl succinate (dry vitamin E) has been shown to reduce the abundance of androgen receptors in prostate cancer cells.¹⁹

Research also indicates that increasing the quantity of gamma-tocopherol slows the growth of cancer cells, and indicates that the anticancer effect is enhanced when mixed forms of tocopherols are used.²⁰ High concentrations of gamma-tocopherol, the most common dietary form of vitamin E (found in seed oils such as sea buckthorn, walnut, and pumpkin), are associated with a statistically significant reduction in the risk of PC.²¹ Along with gamma-tocopherol, recent laboratory research indicates that delta-tocopherol has a potent inhibitory effect on prostate cancer cells, both in hindering growth and stimulating apoptosis.²²

Additional research indicates that vitamin E succinate, recognized as the most effective form of the vitamin, acts in numerous ways to thwart cancer, including inhibiting tumor inducing NF-kappaB. Vitamin E succinate supplementation also decreases the expression of anti-apoptotic proteins and sensitizes androgen-dependent cells to androgen deprivation.²³ Research shows that either vitamin E succinate or selenium alone leads to a modest inhibition in the viability and growth of prostate cancer cells. However, a combination of the two results in a dramatic increase in the inhibition of prostate cancer cells, inducing apoptosis through Bax and Bcl-2 modulation.²⁴ I only use the dry succinate form and dose it 200-400 IU. Often, redox cycling combination formulas provide 200 IU of dry E.

Combining botanicals with antioxidant nutrients can also provide an important edge in managing prostate cancer. An interesting trial investigated the effects of selenium and silymarin (from milk thistle seed) on men who had undergone radical prostatectomy. Thirty-seven participants, 2–3 months after surgery, were randomly assigned to receive 570 mg of silymarin and 240 μg of selenium as selenomethionine or placebo daily. Six months administration of silymarin and selenium improved Quality of Life score, decreased low-density lipoproteins (LDL) and total cholesterol and increased serum selenium levels. No adverse events were recorded, and there was no improvement in the placebo group. This finding is significant because both LDL and total cholesterol are associated with PCa progression, which suggests that selenium and silymarin may be effective in reducing PCa progression.²⁵

And lastly, in a paper reviewing some of the major and most recent findings on the therapeutic properties of three widely used compounds—saw palmetto, lycopene and selenium—the researchers concluded that all three inhibit prostate cancer through the dual activities of inhibiting proliferation and inflammation within the prostate gland.²⁶

Combining botanicals and nutrients is a foundational aspect of my clinical practice, and in my experience, delivers the best results. I have spent the past 25 years evaluating the most current research on botanicals, nutrients, and cancer. In my opinion, the article presented in Medscape was shortsighted and biased against antioxidants, for reasons unknown to me. I hope the information that I’ve presented here, carefully evaluated and culled from decades of research and practice, will prove beneficial.

Research

1. Kristal A, Darke A, et al. Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk. J Natl Cancer Inst. Published online February 22, 2014.
2. Taylor PR, Parnes HL, et al. Science peels the onion of selenium effects on prostate carcinogenesis. J Natl Cancer Inst. 2004 May 5;96(9):645-7.
3. Yoshizawa K, Willett WC, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998 Aug 19:90(16):1219-24.
4. Brooks JD, Metter EJ, et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol 2001 Dec;166(6):2034-8.
5. Meyer HA, Hollenbach B, et al. Reduced Serum Selenoprotein P Concentrations in German Prostate Cancer Patients. Cancer Epidemiol Biomarkers Prev. 2009 Aug 18.
6. Klein EA Selenium – epidemiology and basic science. J Urol 2004 171: S50-S53.
7. Duffield-Lillico AJ et al. Se supplementation, baseline plasma Se status, and incidence of prostate cancer: an analysis of the complete treatment period of the nutritional prevention of cancer study group. British J Urol Intl 2003 91: 608-612.
8. Dong Y et al. Delineation of the molecular basis for Se-induced growth arrest in human prostate cancer cells by oligonucleotide array. Cancer Res 2003 63: 52-59.
9. Zhao H et al. Diverse effects of methylseleninic acid on the transcriptional program of human prostate cancer cells. Mol Biol Cell 2004 15: 506-519.
10. Zu K, Ip C. Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells. Cancer Res 2003 63: 6988-6995.
11. Corcoran NM, Najdovska M, et al. Inorganic Selenium Retards Progression of Experimental Hormone Refractory Prostate Cancer. The Journal of Urology February 2004 171:2:1: 907–910.
12. Waters DJ et al. Effects of dietary Se supplementation on DNA damage and apoptosis in canine prostate. J Natl Cancer Inst 2003 95: 237-241.
13. Gianduzzo TR et al. Prostatic and peripheral blood selenium levels after oral supplementation. J Urol 2003 170: 870-873.
14. Drasch G, Schöpfer J, et al. Selenium/cadmium ratios in human prostates: indicators of prostate cancer risk of smokers and nonsmokers, and relevance to the cancer protective effects of selenium, Biol Trace Elem Res. 2005 Feb;103(2):103-7.
15. Li H, Kantoff PW, Giovannucci E, et al. Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. Cancer Res. 2005 Mar 15;65(6):2498-504.
16. Neill MG, Fleshner NE. An update on chemoprevention strategies in prostate cancer for 2006. Curr Opin Urol. 2006 May;16(3):132-7.
17. Weinstein SJ, Wright ME, et al. Serum and dietary vitamin e in relation to prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1253-9.
18. Ozmen H, Erulas FA, et al. Comparison of the concentration of trace metals (Ni, Zn, Co, Cu and Se), Fe, vitamins A, C and E, and lipid peroxidation in patients with prostate cancer. Clin Chem Lab Med. 2006;44(2):175-9.
19. Zhang H, Wu Y, Malewicz B, et al. Augmented suppression of androgen receptor signaling by a combination of alpha-tocopheryl succinate and methylseleninic acid. Cancer. 2006 Nov 21.
20. Helzlsouer, KJ. Levels of vitamin E –gamma-tocopherol associated with a significant reduction in prostate cancer. J Natl Cancer Inst. 2000; 92:1966-1967, 2018-2023.
21. Wong, J, Fyrst, H, et al. Vitamin E in plant seeds could halt prostate, lung cancer, © 2004 NewsRx.com. December 30, 2004.
22. Huang H, He Y, et al. Potent Inhibitory Effect of δ (Delta)-Tocopherol on Prostate Cancer Cells Cultured in Vitro and Grown As Xenograft Tumors in Vivo. J Agric Food Chem. 2014 Oct 27.
23. Crispin PL, Uzzo RG, et al. Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate. 2007 May 1;67(6):582-90.
24. Regan-Shaw S, Nihal M, et al. Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio. Prostate. 2008 Nov 1;68(15):1624-34.
25. Vidlar A, Vostalova J, et al. The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy – a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Sep;154(3):239-44.
26. Magri V, Trinchieri A. Activity of Serenoa repens, lycopene and selenium on prostatic disease: evidences and hypotheses. Arch Ital Urol Androl. 2008 Jun;80(2):65-78. Review.