Prostate Cancer and Antioxidants
By Gerald T. Keegan, MD, FACS, and Lynn Keegan, RN, PhD, HNC-BC, FAAN. Dr. Gerald Keegan is Emeritus Staff, Scott & White Clinic and Hospital, and former Professor of Surgery (Urology), Texas A&M, University School of Medicine, Temple, TX; Dr. Lynn Keegan is Director, Holistic Nursing Consultants, Port Angeles, WA. Drs. Keegan report no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Prostate cancer is the most common non-skin cancer among American men. Estimates suggest that more than 230,000 new cases of prostate cancer are diagnosed annually in the United States and that about 30,000 men will die annually of the disease.1,2 Data for 2004 indicate that prostate cancer will account for 20% of all cancer cases in the United States compared with 19% for breast cancer, 16% for lung cancer, and 13% for colorectal cancer.2 The incidence of newly diagnosed prostate cancer has been variable over the past few decades, in part due to increased frequency of prostate screening3 via measurement of prostate-specific antigen (PSA) levels, but also due to early diagnosis by safe and readily available ultrasonic biopsy techniques, both making statistical comparison difficult. In addition, estimates of prostate cancer incidence are confounded by autopsy evidence of microscopic disease in 30% of men older than age 50, and in 70% of men who are 80 years of age or older, as well as the widespread tendency to biopsy more patients. For a 50-year-old man with a life expectancy of 25 years, the lifetime risk of microscopic prostate cancer is about 42%, the risk of clinically evident prostate disease is 10%, and risk of fatal prostate cancer is 3%.4
Based on this information, it is clear that there are a number of cases of microscopic prostate cancer that never become clinically apparent. The question then arises as to whether there are factors that trigger the manifestations of the disease process and whether this triggering process can be prevented or modified.
Etiology of Prostate Cancer
Like most cancers, the ultimate cause of prostate cancer is unknown and likely multifactorial, but manifold sequential events over a period of years probably play initiating roles in producing the disease. For most cancers, the first step in carcinogenesis involves mutation in the genetic makeup of a cell's DNA, such as loss of a suppressor gene. The cell then develops further abnormalities under the influence of a cancer promoter, which also stimulates abnormal growth.
Definitive risk factors for prostate cancer include age, genetics, family history, and race. The incidence and mortality from prostate cancer increase exponentially after age 50.5,6 The risk of an individual developing prostate cancer depends not only on the number of affected relatives, but also upon the age at which they developed the disease.7,8 In the United States, black men have a higher incidence rate of prostate cancer than white men of similar education and socioeconomic group, and are generally diagnosed with later stage disease and have a lower survival rate even when correlated for stage.9 Probable risk factors include dietary fat, hormonal status, tobacco use (perhaps secondary to excess accumulation of cadmium), and exposure to other toxic agents. Prostate cancer mortality rates in the United States are inversely proportional to ultraviolet radiation exposure, which is necessary for the synthesis of vitamin D. Prostate cancer is more common in Northern countries.10
Some question whether there may be potential risk with high intake of calcium. One study found that calcium may support vitamin D-related antiproliferative effects in prostate cancer.11 Another investigation examined the association of dairy, calcium, and vitamin D intake with prostate cancer. In a prospective study of 3,612 men followed from 1982-1984 to 1992 for the first National Health and Nutrition Examination Epidemiologic Follow-up Study, 131 prostate cancer cases were identified. Dietary intake was estimated from questionnaires completed in 1982-1984. Relative risk and 95% confidence intervals were estimated by using Cox proportional hazards models adjusted for age, race, and other covariates. The researchers concluded that dairy consumption may increase prostate cancer risk through a calcium-related pathway.12
On the other hand, an Italian study of 1,294 men with incident prostate cancer showed no material association of dietary intake of calcium, vitamin D, and phosphorus with prostate cancer risk.13 In a Dartmouth Medical School study of 672 men in a randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect.14
Concepts of Chemoprevention of Prostate Cancer
Multiple substances have been recommended to prevent the development of clinically evident prostate cancer, as well as to reverse the precancerous lesion known as prostatic intraepithelial neoplasia (PIN). Chemopreventive agents can be classified into several major types based upon their presumed mechanism of action. These include inhibitors of initiation, antipromotional agents, and inhibitors of progression. Prostate cancer is characterized by a very long period of development, and for this reason, chemoprevention and chemosuppression appear to be real possibilities.15 Because of the hormonal dependence of prostate cancer, one substance that has been studied and found in clinical trials to potentially prevent prostate cancer development is finasteride, an agent that prevents the conversion of testosterone into its active form of dihydrotestosterone by inhibition of 5-alpha reductase.16
Although the risk of prostate cancer was reduced by 25% in men who took finasteride in the Prostate Cancer Prevention Trial, a large-scale study of chemoprevention for prostate cancer, those cases of prostate cancer that emerged during this trial were characterized by a higher grade cancer. There has been considerable dispute as to whether these findings truly represent a higher grade prostate cancer or whether they simply represent histological artifact or earlier diagnosis with lead time bias. A model has been developed at the University of Texas in San Antonio that will weigh potential benefits against potential risks considering the factors of both histological artifact induced by the use of finasteride (which may produce cellular changes resembling higher grade prostate cancer) as well as earlier detection (and possibly over-detection) of the disease.17
Toremifene, a selective estrogen receptor modulator, used for the treatment of metastatic adenocarcinoma of the breast in women, has been found to prevent the progression of high-grade PIN into prostate cancer.18 Various other studies are ongoing including extensive studies of the effects of vitamin D, anti-inflammatory agents, and soy-based isoflavonoids in prostate cancer prevention.
The focus of this article, however, will be on antioxidant agents. Specifically, we will look at vitamins E and C, selenium, and lycopene.
Mechanisms of Action of Antioxidants
In evaluating any agent thought to prevent prostate cancer, proposing a mechanism of action is helpful in developing understanding. However, it is likely that most preventive substances act in many ways, not solely by a solitary mechanism. One potential mechanism of action involves the transformation of a normal cell into one with malignant potential by the loss of a tumor-suppressor gene.
Oxidative stress also may produce alterations in cellular DNA. The molecular mechanisms that lead to increased susceptibility of tissues to oxidative stress are not well understood.
Researchers at the Robert Wood Johnson Medical School have reported a link between loss of protection against oxidative damage and loss of function of Nkx3.1, a gene known to be required for prostatic epithelial differentiation and suppression of prostate cancer. Using gene-expression profiling, they found that Nkx3.1 mutant mice display deregulated expression of several antioxidant enzymes disproportionate to the deregulation of the pro-oxidant enzymes, including glutathione peroxidase 2 and 3 (GPx2 and GPx3), peroxiredoxin 6 (Prdx6), and sulfhydryl oxidase Q6 (Qscn6). Moreover, the formation of PIN in these mutant mice was associated with increased oxidative damage of DNA, as evident by increased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG). They also showed that progression to prostate adenocarcinoma was correlated with a further deregulation of antioxidants, including superoxide dismutase. Their findings suggest a molecular link between a gene whose inactivation is known to be involved in prostate carcinogenesis, namely Nkx3.1, and oxidative damage of the prostatic epithelium.19 In summary, it is possible that one of the mechanisms contributing to the development of prostate cancer is oxidative stress that results in deletion of a tumor suppressor gene.
Scientists from the University of California (Davis) have hypothesized that lysosomal enzymes and prostasomes (biologically active organelles secreted by prostate epithelial cells) are released from prostate cells into the duct system of the prostate, where their hydrolytic enzymes and associated oxidative processes damage proteins and other cell components, leading to carcinogenesis. Risk factors, such as ionizing radiation, oxidative stress, environmental toxins, and diets high in saturated fat content may initiate activity of lysosomal or prostasomal enzymes. Dietary components in fruits and vegetables, which are thought to protect against prostate cancer, may work by decreasing cellular output of lysosomal or prostasomal enzymes, or through inhibition of lysosomal and prostasomal enzymes in the duct system. The authors also suggest protection against prostate cancer by inhibitors of lipid peroxidation, including the dietary antioxidants selenium, vitamin E, and lycopene, and also cysteine glutathione.20
The next question to be explored is whether any evidence exists to support the hypothesis that antioxidants prevent or reverse oxidative stress.
In the experimental animal model, oxidation may damage the cell by causing deletion of cancer-suppressing genes, and such damage may be prevented, or at least ameliorated, by the use of antioxidants.21-23 A discussion of the clinical evidence suggesting a role for these agents in human nutrition, again realizing that the effects of such agents may be multifocal and not solely based on their antioxidant potential, follows.
The results of the 13-year Nutritional Prevention of Cancer Trial confirmed that selenium supplementation is associated with marked reductions in cancer risk (all-site except skin), including cancers of the prostate and colon-rectum (the effect on diminishing the incidence of prostate cancer was quite significant).24
Preclinical, epidemiological, and Phase III data from two randomized, placebo-controlled clinical trials suggest that both selenium (l-selenomethionine) and vitamin E (alpha-tocopherol) have potential efficacy in prostate cancer prevention.25 The ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT), sponsored by the National Cancer Institute, is a Phase III, randomized, double-blind, placebo-controlled, population-based clinical trial designed to test the efficacy of selenium and vitamin E alone and in combination to prevent prostate cancer. Randomization will be equally distributed among the four study arms, with intervention consisting of a daily oral dose of study supplement (200 µg l-selenomethionine and/or 400 mg of racemic alpha-tocopherol) or matched placebo. Study duration is planned for 12 years, with a five-year uniform accrual period. The primary endpoint for SELECT is the clinical incidence of prostate cancer as determined by routine clinical diagnostic work-up, including yearly digital rectal examination of the prostate and serum PSA level. SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment began in 2001, with final results anticipated in 2013. The motivating concept underlying this study is related directly to in vitro evidence suggesting that selenium and vitamin E work synergistically to cause cell-cycle arrest, induce caspase-mediated apoptosis, and act as antiandrogens in arresting clonal expansion of nascent tumors.26
Another study at the University of Massachusetts Medical School complements the currently ongoing Selenium and Vitamin E Cancer Prevention Trial. The objective was to determine the effects of selenium and vitamin E in blood and prostate tissue in patients with clinically localized prostate cancer. Patients were randomized to take selenium, vitamin E, both, or placebo for 3-6 weeks before prostatectomy. Thirty-nine patients were evaluable, and 29 age-matched disease-free men served as controls. Sera were collected from patients before and after dietary supplementation. Analyses showed a change in sera classification from cancerous to healthy for some patients with prostate cancer after dietary intervention. In sera from patients with prostate cancer, the selenium and vitamin E combination induced statistically significant proteomic (the analysis of serum marker proteins) pattern changes comparable with prostate cancer-free patients.25
Researchers in Canada assessed whether supplementation with low doses of antioxidant vitamins and minerals could reduce the occurrence of prostate cancer and influence biochemical markers. The SU.VI.MAX trial included 5,141 men randomized to take either a placebo or supplement containing vitamin C, vitamin E, beta-carotene, selenium, and zinc daily for eight years. Biochemical markers of prostate cancer risk such as PSA and insulin-like growth factors (IGFs) were measured on plasma samples collected at enrollment and at the end of follow-up from 3,616 men. During the follow-up, 103 cases of prostate cancer were diagnosed. Overall, there was a moderate, but nonsignificant reduction in prostate cancer rate associated with supplementation. However, the effect differed significantly between men with normal baseline PSA and those with elevated PSA. Among men with a normal PSA, there was a markedly significant reduction in the rate of prostate cancer for those receiving the supplements. Supplementation had no effect on PSA or IGF levels. The findings support the hypothesis that chemoprevention of prostate cancer can be achieved with supplementation of antioxidant vitamins and minerals.27
Few studies have provided information on isolated study of antioxidant vitamins independent of one another, but a group at Johns Hopkins University assessed whether higher prediagnostic plasma concentrations of vitamin C were associated with a lower risk of prostate cancer in a well-nourished cohort of men. Total plasma ascorbic acid (L-ascorbic acid plus dehydro-L-ascorbic acid) levels were measured. Among the 498 male participants with measured plasma vitamin C levels, 62 were subsequently diagnosed with prostate cancer during their lifetime. The authors concluded that higher plasma vitamin C concentrations within the normal physiologic range are not associated with a lower risk of prostate cancer in well-nourished men, and that vitamin C as a single agent was not protective against prostate cancer.28
Further evidence of the chemopreventive effects of alpha-tocopherol and l-selenomethionine comes from secondary analysis of two Phase III clinical trials,25 but there have been studies of the effects of vitamin E as a solitary agent. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study demonstrated a 32% reduction in prostate cancer incidence in response to daily alpha-tocopherol supplementation. The baseline serum concentrations of alpha-tocopherol and gamma-tocopherol were studied to compare their respective associations with prostate cancer risk. From the ATBC study cohort of 29,133 Finnish men, 50-69 years old, 100 incident prostate cancer case patients and 200 matched control subjects were randomly selected. Further analyses indicated that the association of high serum tocopherols with low prostate cancer risk was stronger in the alpha-tocopherol-supplemented group than in those not receiving alpha-tocopherol.29
A study from the University of Texas Health Science Center at San Antonio gleaned data from the Prevention Research Veteran Affairs E-vitamin Nutrition Trial. This randomized, double-blind, placebo-controlled study was designed to assess the effects of vitamin E supplementation on biomarkers associated with prostate cancer risk in peripheral blood and prostate tissue. Forty-four patients with increased PSA and/or abnormal digital rectal examination on initial evaluation were randomized to receive 400 IU vitamin E (22) vs. placebo (22). Serum vitamin E, PSA, dehydroepiandrosterone, testosterone, and IGF-1 were measured in the two groups at baseline and then at three-month intervals. Serum vitamin E was significantly higher in patients on vitamin E supplementation. Alpha-tocopherol supplementation did not affect PSA levels, serum androgens (testosterone and dehydroepiandrosterone), or IGF-1. The results suggest that any decrease in prostate cancer risk with alpha-tocopherol is likely to occur through a mechanism that is non-hormonal and independent of IGF-1.30
The question arises as to which form of vitamin E is most effective as a preventive agent. Studies of the effects of gamma-tocopherol, the predominant vitamin E form in diets, but not alpha-tocopherol, which is the exclusive form of vitamin E in most supplements, on prostate tissue culture were performed at Purdue University. Gamma-tocopherol exhibited an antiproliferative effect on prostate and lung cancer cells, and induced apoptosis in androgen-sensitive prostate cancer, but not in androgen-resistant cells. Gamma-tocopherol treatment caused cytochrome c release and caspase-9, -3 and -7 activation. However, apoptosis could not be completely reversed by a pancaspase inhibitor, indicating that an alternative caspase-independent pathway may also be involved. This study suggests an independent effect of gamma-tocopherol in the prevention and treatment of certain types of prostate cancer.31
The effect of tomato-derived lycopene as a prostate cancer preventive has been discussed extensively in the in the lay literature, but as yet, most information has been derived from epidemiological studies. One meta-analysis performed to determine whether intake of tomato products reduces the risk of prostate cancer employed a systematic MEDLINE and EMBASE search and identified 11 case-control studies and 10 cohort or nested case-control studies. The results showed that tomato products may play a role in the prevention of prostate cancer. The effect was modest and restricted to high amounts of tomato intake.32
In contrast, a small study performed to assess the biochemical effects of tomatoes in patients about to undergo prostatectomy for prostate cancer did show significant benefit. Tomato sauce pasta was consumed daily for three weeks before their scheduled procedures. Biomarkers of tomato intake, prostate cancer progression, and oxidative DNA damage were followed in blood and the available prostate tissue. Oxidative DNA damage in leukocytes and prostate tissues was significantly diminished, possibly due to the antioxidant properties of lycopene. Remarkably, there was a decrease in blood PSA, which was explained by the increase in apoptotic death of prostate cells, especially in carcinoma regions. Possible explanations for these promising results may reside in lycopene's effects on the genes governing androgenic stimulation of prostate growth, effects on cytokines, and effects on the enzymes producing reactive oxygen species. Other phytochemicals in tomatoes and tomato-based products may act in synergy with lycopene to potentiate protective effects.33 The above study focused on men with prostate cancer who consumed tomato sauce prior to having a radical prostatectomy. The effects of the tomato sauce produced a regression in the measurable parameters of prostate cancer activity. By a process of analogous reasoning, we can postulate that with the high incidence of prostate cancer cells present in a large percentage of older men the activity of those cells may be significantly retarded by the use of tomato-based products.
There are no specific contraindications to intake of antioxidants from foods; however, excessive dosages of any one substance can be detrimental. The best source of most antioxidants is from natural food substances, but as noted above, proprietary selenium supplements are essential. A concern about the toxicity of selenium has limited the doses used in chemoprevention. To assess this toxicity scientists at Roswell Park Cancer Institute investigated the plasma response and toxicity reports from 24 men with biopsy-proven prostate cancer who were randomized to either 1,600 or 3,200 µg/d of selenized yeast as part of a controlled clinical trial testing selenium as a chemopreventive agent for prostate cancer progression. The 3,200 µg/d group reported more selenium-related side effects, but none was deemed serious.34 However, as noted above, higher doses of selenium may not be additionally advantageous in the prevention of prostate cancer.23
There has been a spate of recent articles in the literature on the hazard of using high-dose vitamin E in excess of 400 IU/d. A randomized, double-blind, clinical trial of the effects of vitamin E supplementation on cancer and heart disease came up with some astounding findings. Although this study showed no difference in the incidence of cancers or cancer-related deaths between the vitamin E and the placebo groups, there was a 19% increase in the risk of heart failure and a 40% increase in hospital admissions in the vitamin E group.35 The study suggests that patients with established cardiovascular disease are not good candidates for vitamin E supplementation. Based upon reviews of the literature, the maximum recommended daily dose of vitamin E is 400 IU, while that for selenium is 200 µg, and for vitamin C is 2 g in completely healthy individuals.
Selenium and vitamin E are the most accepted dietary supplements considered for use in the reduction of prostate cancer risk. This enthusiasm is reflected in the initiation of the Selenium and Vitamin E Chemoprevention Trial (SELECT). Results from numerous laboratory and observational studies support the use of these supplements, and data from recent prospective trials add some support. To err on the side of caution, a closer analysis of these data reveals some interesting and unique associations. Selenium supplements provided a benefit only for those individuals who had lower levels of baseline plasma selenium. Other subjects, with normal or higher levels, did not benefit and may have an increased risk for prostate cancer. The concept that supplements reduce prostate cancer risk only in those at a higher risk and/or those with lower plasma levels of these compounds is supported by trials examining beta-carotene supplements. In four recent prospective studies, vitamin E was found to reduce the risk of prostate cancer in past/recent and current smokers and those with low levels of this vitamin. Vitamin E supplements in higher doses (≥ 100 IU) were also associated with a higher risk of aggressive or fatal prostate cancer in nonsmokers from a past prospective study.36
Although the optimal dosages of many antioxidant compounds and the assessment of their blood and tissue levels in individuals has not as yet been established, there is ample evidence to suggest that a low-dose and inexpensive multivitamin taken daily may reduce all-cause mortality and cancer risk, especially in healthy men who do not consume a highly diverse quantity of fruits and vegetables. A randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals involving 13,000 French adults followed for 7.5 years showed that although there was no clear-cut effect of taking these supplements in women in terms of reducing their risk of cancer or cardiovascular disease, a significant protective effect was found in men. Men in this study reduced their risk of any cancer by 31% and their risk of all-cause mortality by 37%. The low-dose multivitamin in this trial consisted of 120 mg ascorbic acid, 30 mg of vitamin E, 6 mg of beta-carotene, 100 µg of selenium, and 20 mg of zinc.37
The dose of vitamin E in the SELECT trial (400 IU/d) is eight times higher than what has been suggested to be effective (50 IU/d) by the largest randomized prospective trial in which the incidence rate of prostate cancer was used as an endpoint. Recent research also suggests that dietary vitamin E may be associated with a lower risk of prostate cancer than the vitamin E supplement.36
The best approach, therefore, is a natural one and whenever possible men should try to use whole food sources. Even though the evidence does not clearly indicate benefit, we recommend increased consumption of tomato-based products.
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