Chemoprevention and Prostate Cancer

Prostate cancer is unique in that its behavior may vary greatly between different patients.¹ Although prostate cancer may be present histologically in nearly 30% of all men above the age of 50 years, the lifetime risk of developing clinically significant prostate cancer is less than 12%.^2,3 Furthermore, the lifetime risk of dying from prostate cancer is less than 4%.^2,3 Thus, the development of an effective chemopreventative measure for prostate cancer would greatly affect the natural history of this important disease.

Prevention is always better than cure. To this effect, recently there has been a great deal of interest generated in prostate cancer chemoprevention, which is defined as the administration of natural or synthetic agents (pharmaceuticals, biologics, and micronutrients) to prevent initiation, inhibit promotion, or delay progression from normal-appearing prostate epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive adenocarcinoma and metastatic systemic disease.⁴ The selection of agents to be tested in patients for primary or secondary prostate cancer prevention is based on evidence gathered from epidemiologic, experimental, and clinical studies.

Numerous agents are currently under clinical evaluation and may in the future provide a source for preventing the development of clinically significant prostate cancer. Among these agents, selenium, vitamin E, and lycopene hold special interests. A study consisting of more than 29,000 Finnish male smokers revealed that vitamin E (50 IU of dl-alpha tocopherol) was found to be associated with a 32% reduction in prostate cancer.⁵ Another study consisting of more than 1300 men and women at a high risk of developing recurrent nonmelanoma skin cancer revealed that selenium (200 μg of selenized yeast) was associated with a marked reduction in the incidence of prostate cancer (67% reduction).⁶

These studies, despite their limitations and bias, have lead to the decision by the National Institutes of Health to sponsor the Selenium and Vitamin E Chemoprevention Trial (SELECT), which will consist of four arms: selenium versus vitamin E versus selenium and vitamin E versus placebo.⁷ It is hoped that approximately 32,000 men, with no history of prostate cancer or HGPIN and 55 years of age or older (50 years of age or older if African American), will be recruited into the study from 300 different sites. The study will be conducted for 7–12 years.

Lycopene has also generated a great deal of interest, as there is conflicting evidence regarding its association with a reduction in prostate cancer risk.⁸ The exact mechanism of action of both vitamin E and selenium in tumor prevention is not well established. Two recent studies, reviewed below, shed some light on this matter. The final article reviewed here provides further evidence for the role of lycopene in prostate cancer chemoprevention.

Vitamin E Succinate Inhibits the Function of Androgen Receptors and the Expression of Prostate-Specific Antigen in Prostate Cancer

Zhang Y, Ni J, Messing EM, et al.

Proc Natl Acad Sci U S A. 2002;99:7408–7413.

Epidemiological evidence supports the beneficial effect of daily vitamin E supplement in reducing the risk of prostate cancer; however, the underlying mechanism involved is not well established. Using the human prostate cancer cell line LNCaP (derived from lymph node prostate cancer metastasis), the authors have demonstrated that α-tocopheryl succinate (VES; 10 μM) effectively inhibited the growth of these cells. On the other hand, hydroxyflutamide (HF; 5 μM), an antiandrogen, only had a slight inhibitory effect. However, the combination of both VES and HF more significantly inhibited the cells than either agent alone. Using Western and Northern blotting analyses, the authors have also demonstrated that 10 mM of VES effectively repressed prostate-specific antigen (PSA) expression at both the mRNA and protein levels in LNCaP cell cultures. In addition, using Northern blotting they have also shown that VES also suppressed androgen receptor expression by means of transcriptional and post-translational modulation. This VES-mediated inhibition of androgen receptor expression appears to be selective, as VES did not repress the expression of other nuclear receptors. Hence, the authors have concluded that VES may suppress androgen/androgen receptor-mediated cell growth and PSA expression by inhibiting androgen receptor expression at both the transcription and translation levels.

This study provides credible preliminary evidence for the underlying mechanism of action of vitamin E-mediated inhibition of prostate cancer cells. This may, in turn, help us to establish new therapeutic concepts for the prevention and treatment of prostate cancer.

Selenium Modulation of Cell Proliferation and Cell Cycle Biomarkers in Human Prostate Carcinoma Cell Lines

Venkateswaran V, Klotz LH, Fleshner NE.

Cancer Res. 2002;62:2540–2545.

Venkateswaran and colleagues assessed whether selenium inhibits cell growth and associated cell cycle regulatory proteins. Human prostate cancer cell lines (LNCaP, PC3, PC3-AR2, and PC3-M) were incubated in the presence and absence of selenium (selene-DL-methionine, 150 mM) for 24, 48, and 72 hours. Cells were then fixed and stained with propidium iodide for flow cytometry analysis. Selenium produced a time- and dose-dependent arrest of LNCaP cells in G₁ and an 80% reduction in the S-phase. Selenium, on the other hand, had no effect on PC3 cells. However, PC3 cells transfected with the androgen receptor (PC3-AR2) exhibited a G₂/M arrest and a marked reduction (57%) in the S-phase during cell cycle progression.

Defects in the regulation of cell cycle progression are regarded as common features of transformed cells. Eukaryotic cell cycle progression is regulated by a series of cyclin-dependent kinases, their activity positively regulated by cyclins and negatively regulated by cyclin-dependent kinase inhibitors (CKIs). The significance of growth factors and the signalling pathways mediated by them to regulate the progression of cell cycle in eukaryotes has been identified as an important component of their function. Hence, these authors, using Western blot techniques, also assessed whether inhibition of cell growth was associated with alterations in cell cycle regulatory molecules. Their results demonstrated that selenium-treated cells exhibited a time-dependent significant up-regulation of CKIs Cip1/p21 and Kip1/p27.

In conclusion, this study has shown that selenium possesses strong prostate cancer antiproliferative properties, which appears to be dependent on the presence of a functioning androgen receptor. The authors have also provided some evidence for the possible underlying mechanisms that may play a role in selenium-associated prostate cancer cell anti-proliferation.

A Prospective Study of Tomato Products, Lycopene, and Prostate Cancer Risk

Giovannucci E, Rimm EB, Liu Y, et al.

J Natl Cancer Inst. 2002;94:391–398.

In view of the conflicting evidence of the association between tomato products or lycopene, a carotenoid from tomatoes, and prostate cancer risk, these authors evaluated additional data from the Health Professionals Follow-Up Study (HPFS) to further determine whether there is indeed an association between lycopene intake and a reduction in prostate cancer risk. They ascertained prostate cancer cases from 1986 to January 31, 1998, among 47,365 HPFS participants who completed dietary questionnaires in 1986, 1990, and 1994. They found that during the study period 2481 men developed prostate cancer. Results for the period from 1992 through 1998 confirmed their previous findings that frequent tomato or lycopene intake was associated with a reduced risk of prostate cancer.⁹ Similarly, for the entire period of 1986 through 1998, from taking the cumulative average of the three dietary questionnaires, the authors further determined that lycopene intake was associated with reduced risk of prostate cancer (relative risk [RR] for high vs low quintiles = 0.84; 95% confidence interval [CI] = 0.73–0.96; P_trend < .001), especially for extraprostatic cancer (RR = 0.65; 95% CI = 0.42–0.99). These associations persisted in analyses controlling for fruit and vegetable consumption, as well as for the use of olive oil.

The conclusion drawn from this large epidemiological study is that frequent consumption of tomato products is associated with a lower risk of prostate cancer; however, as the magnitude of this association is only moderate, it is possible to miss this association in a small study.