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Monday, July 9, 2007

Lycopene, Selenium and Vitamin E in Combination for Prostate Cancer

[Updated January 3, 2010]

Note that since the information on this page was written a large scale study, the SELECT trial, concluded that selenium and vitamin E do not reduce the risk of prostate cancer (at least in the dosages used). See [SELECT Q&A]. Also a second large scale trial just reported that "individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily" did not prevent cardiac events (i.e. heart attack, stroke). [PMID: 18997197] [Full Text]. The November 20, 2008 New York Times' blog ran a story summarizing the latest news: [link]. Fleshner et al who performed the research below themselves announced negative results on the benefit of E combined with selenium and soy. [news release] at the 2009 AUA Annual meeting.

These negative results not withstanding in the following paper the same authors do hold out hope that further studies may still show benefits. See [PMID: 19997071].

Readers interested in nutrition and prostate cancer may also wish to read Zlotta's October 2008 comment [PMID: 18953448] [Full Text] and the following posts on this site:

Vitamin D and Prostate Cancer
Holick's July 2007 NEJM Paper on Vitamin D
Canadian Cancer Society Recommends 1000 IU/day Vit...
WCRF/AICR Diet and Cancer Report
Lycopene, Selenium and Vitamin E in Combination fo...
How Healthy Men Can Reduce Their Risk
Diet Soft Drinks

In a 2007 ASCO presentation Neil Fleshner (who is also co-author of one of the free nutrition downloads, Prostate Cancer Nutrition and You listed in the right hand column of this blog) cites results in both mouse models and in human subjects where consuming a combination of:
  • lycopene (50 mg/day)
  • selenium (200 mcg/day)
  • vitamin E (800 IU/day)
or the mouse equivalent virtually arrested prostate cancer development in mice and in only 4 weeks brought about improvements in progression markers in humans. A key observation of this study is that the combination of antioxidants is far more beneficial than treatment with any single antioxidant alone.

Human Trial

The human trial consisted of 50 subjects with prostate cancer divided into 5 groups: no supplementation, vitamin E group (800 IU/day), selenium group (200 mcg/day), lycopene group (50 mg/day) and a group given all three. After 4 weeks there was virtually no Ki67 staining (a proliferative marker) on the combination antioxidant group suggesting that prostate cancer was virtually arrested in only 4 weeks. In the single antioxidant groups only selenium showed an improvement over the control but nowhere near the combination treatment. Except for the combination group staining was seen in all groups. Also, there was dramatic upregulation of p27 in both the cytoplasm and the nucleus in the combination treatment. (p27 is a cell cycle inhibitor that is associated with prolonged survival.)

Animal Study

The animal study discussed was from a 2004 Cancer Research paper [FullText] [PMID: 1531393]. In that study 19 transgenic mice, bio-engineered to develop prostate cancer, were put on a standard diet and of the 19 mice 14 did, in fact, develop prostate cancer. On the other hand only 2 of 19 similar bio-engineered transgenic mice on the same diet but supplemented with lycopenes, selenium and vitamin E developed prostate cancer. The difference between 14 of 19 and 2 of 19 is highly statistically significant. The investigators also tried putting mice on a high fat diet (40% of calories derived from fat) in which case all 19 of 19 mice developed prostate cancer but only 3 of 19 whose high fat diet was supplemented with lycopenes, selenium and Vitamin E. The difference between 19 of 19 and 3 of 19 is also highly significant, statistically. One interesting observation that these numbers illustrate is that the antioxidants were not only beneficial in preventing prostate cancer but also largely blocked the negative effect of a high fat diet. There was no evidence of antioxidant-related toxicity in the mice given the antioxidants. The antioxidant dosages were provided in the human equivalent to 800 IU Vitamin E, 200 mcg selenium and 50 mg of lycopene per day.

A 2008 animal study that examined the effect of combined selenium and isoflavones on rats also concluded that taking them together had a large favorable effect on the amount later detected in the blood stream relative to separate administration of the two. See [PMID: 19000315] [provisional text].


Vitamin E. Although no toxicities were observed in this study,
  • a meta analysis of other studies concluded that Vitamin E increased the risk of dying by 39 in 10,000 when taken at a dosage of 400 IU/day or more; however, the conclusion seems controversial and, in particular, some of the studies used multi-vitamins, not just E. See the related articles at the bottom of [link] for discussion on this study.
  • the Womens' Health Study (WHS) concluded that cardiovascular disease increased among users of 600 IU/day of Vitamin E though the increase was not statistically significant. [link]
  • The Heart Outcomes Prevention Evaluation–The Ongoing Outcomes (HOPE-TOO) patients in the vitamin E group had a significantly increased risk for heart failure and hospitalization for heart failure in the Vitamin E group. [link]

Lycopene. High levels of lycopene may have adverse effects in smokers and certain other groups. [link].


  • Diabetes. In a 7.7 year human trial subjects who took 200 mcg/day of selenium increased their risk of developing diabetes by 50% (incidence, 12.6 cases per 1000 person-years vs. 8.4 cases per 1000 person-years for controls). See [PMID: 17620655] [Full Text]. A probability sample done in the US determined that the quartile taking the greatest amount of selenium had a 57% greater probability of developing diabetes than the quartile taking the lowest amount of selenium (however, the quartiles were not monotonically increasing). See [PMID: 17392543].
  • Toxicities not explored. In Bottom Line's "Why Doctors Don't Get Sick", Dr. Victor Herbert of the Mount Sinai School of Medicine in New York is said to have commented on the Harvard study that indicated selenium reduced the risk of advanced prostate cancer saying that the study failed to look at the incidence of other kinds of cancer, overall death and illness rates. Also there is little evidence that Americans are selenium deficient.
  • More. For more on selenium see [link]. Dr. Marc Garnick (papers) of the Harvard Medical School has written a brief summary of the pros and cons of selenium here. There has been some speculation that selenium might hide rather than prevent prostate cancer.


Doubts on Lycopene Effectiveness. A recent study of 28,000 men concluded that lycopene does not prevent prostate cancer [link] [PMID: 17507623] contradicting previous studies and the FDA has concluded that there is only a limited evidence of association between eating tomatoes and decreased risk of prostate cancer [article], [link]. Giovannucci speculates in [PMID: 17623795] [Full Text] that lycopenes may have more of an effect on later stage cancers when the initial studies that showed association were prevalent but that in today's environment of PSA testing and earlier stage cancer they may be less effective. That would account for the discrepancy in results. Fleshner's study suggests that there is still the possibility that it may be effective in conjunction with other antioxidants.

Another Combo - Brocolli and Tomatoes. Another animal study found positive effects from a combination of broccoli and tomatoes. In that study rats were fed the equivalent of 1.4 cups of raw broccoli and 2.5 cups of fresh tomato per day which had the effect of reducing tumor weight by about half relative to controls. 1 cup of tomato sauce or 1/2 cup of tomato paste would presumably be equivalent to the fresh tomato. See [article] and [PMID: 17213256].

Green Tea Combos. (1) Celebrex. Yet another combination study suggests that 200 mg of Celebrex, a COX-2 inhibitor, and green tea synergistically combine to reduce the growth of prostate tumors by 81% vs 42% for green tea extract alone and 57% for Celebrex along. [review] [PMID: 17332308]. (2) Citurs Juice. A Purdue in vitro (test tube) study concluded that mixing green tea with citrus juice (and to a lesser extent with citric acid, BHT, EDTA, ascorbic acid, milk, soy milk or rice milk) increased the catechin, i.e. active anti-cancer ingredient, recovery significantly. See Purdue press release and [PMID: 17688297] . (3) Soy. A Harvard study found that a combination of tea (either black or green) and soy had synergistic effects against prostate cancer in mice [PMID: 12566493] [full text].

Resveratrol/Quercetin combo. Resveratrol [PMID: 18439064] [PMID: 18414053] has anti-cancer effects against prostate cancer but is made less bioavailable in the liver through sulfation. It was found that this can be counteracted making the Resveratrol more bioavailable if quercetin, mefenamic acid (a non-steroidal anti-inflammatory, NSAID, marketed by Pfizer as Ponstel in the US and Ponstan or Parkemed elsewhere) or salicyclic acid (aspirin, also an NSAID) were simultaneously administered. [PMID: 10923862. Longevinex, a maker of a resveratrol/quercetin combo pill also has information on their site [link]. Note that some caution here is in order with respect to drug interactions. (1) "Older persons who mix alcoholic beverages with large doses of aspirin to self-medicate for pain are therefore at particularly high risk for episodes of gastric bleeding (19). In addition, aspirin may increase the availability of alcohol (31), heightening the effects of a given dose of alcohol. Chronic alcohol ingestion activates enzymes that transform acetaminophen (Tylenol and others) into chemicals that can cause liver damage, even when acetaminophen is used in standard therapeutic amounts (32,33). These effects may occur with as little as 2.6 grams of acetaminophen in persons consuming widely varying amounts of alcohol (34)." according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA): [link]. (2) red wine has inhibitory effects on cytochrome P450 which can result in magnifying the effects of other drugs the user may be taking which may have undesirable effects. [PMID: 11125847]. At higher dosages even more serious drug interaction problems can appear.

Vitamin E. Wright et al [PMID: 1754867] [review], looked at data from the NIH-AARP Diet and Health Study of 295,344 men filled out information on diet. 10,241 developed prostate cancer during 5 years of follow up. There found no connection between Vitamin E supplement (alpha tocopherol) use and prostate cancer risk but found a 32% risk reduction of advanced prostate cancer among the 20% consuming the highest among of Vitamin E (gamma tocopherol) in their diet vs the 20% consuming the lowest amount.

SELECT. There is a large scale 7-12 year cancer prevention study underway on Selenium and Vitamin E called SELECT that enrolled subjects between 2001-2004. See [link] and the references at the bottom of that page. It is expected that better information will become available with it.

Hypoxia-Inducible Factor. A team at John Hopkins has recently discovered that the mechanism by which Vitamin C acts in certain mouse tumors (though not specifically tested in prostate cancer) is to starve them of Hypoxia-Induced Factor (HIF). HIF is a protein that allows cancer cells to grow even in the absence of oxygen so by restricting access to this protein tumors cannot grow without oxygen. It is not known whether this work applies to human prostate cancer or to other antioxidants. See [PMID: 17785204] [John Hopkins news release].

Fleshner's study was previously mentioned on this blog in a revision to the post How Healthy Men can Reduce Their Risk. Even though an animal study and a 4 week study of 50 patients can only be regarded as suggestive, the steps are so easy to take and the results and the combination principle seem sufficiently intriguing that we felt it deserved its own post and so have expanded and moved that discussion here.

In [link] (also found [here]) Fleshner says he recommends 200 IU of vitamin E daily along with selenium to many of his patients who want to do something to lower their risk. "On one hand I am conflicted, because we don’t have the definitive data," he says. "But I have a history of prostate cancer in my family, and I take these agents myself, so I am not telling patients to do anything that I am not doing."

Also, Fleshner and Zlotta have just published a review [PMID: 17893870] on nutrition and prostate cancer in the journal Cancer. A review of that paper can be found here.

According to Medscape, Fleshner owns shares in Bioadvantex which makes supplements including Silexin, that contains lycopene, selenium and Vitamin E (plus other ingredients).

1 comment:

Charles (Chuck) Maack said...

You provided a good wrap-up regarding Lycopene, Selenium and Vitamin E either individually or in combination for prostate cancer. Patients must draw their own conclusions. Personally, I'll opt for the combination since, with 15 years since diagnosis and still a PC patient, the combination supported by the likes of Strum and Myers has been working just fine.