Antioxidants Block Prostate Cancer in Lady Transgenic Mice

Abstract

The development of chemopreventive agents against prostate cancer would benefit from conclusive evidence of their efficacy in animal models that emulate human disease. To date there has been little in vivo evidence supporting their preventive capabilities. The 12T-10 Lady transgenic model spontaneously develops localized prostatic adenocarcinoma and neuroendocrine cancer followed by metastases, recapitulating the natural history of human prostate cancer in many respects. Using male Lady version of the transgenic adenocarcinoma of the mouse prostate mice, we show that administration of antioxidants (vitamin E, selenium, and lycopene) in the diet dramatically inhibits prostate cancer development and increases the disease free survival. Treatment of animals with the antioxidants resulted in a 4-fold reduction in the incidence of prostate cancer compared with the untreated animals. Prostate cancer developed in 73.68% (14 of 19) and 100% (19 of 19) of the animals from the standard and high fat diet, respectively. In contrast, only 10.53% (2 of 19) and 15.79% (3 of 19; P < 0.0001) of the animals in the standard and high fat diets supplemented with antioxidants developed tumors. The micronutrients were well tolerated with no evidence of antioxidant-related toxicity. Histopathological analysis confirmed absence of cancer in the additive treated groups. Immunohistochemistry demonstrated a strong correlation between disease-free state and increased levels of the prognostic marker p27Kip1 and a marked decrease in proliferating cell nuclear antigen expression. These observations provide support for the chemopreventive effect of these micronutrients and some clues as to their mechanism of action.

Methylseleninic acid sensitizes prostate cancer cells to TRAIL-mediated apoptosis

“…Interestingly, among selenium-containing reagents, for example, MSA, sodium selenite, Se-Met and Se-(Methyl)selenocysteine, only MSA sensitized prostate cancer cells to TRAIL-mediated apoptosis (Figure 3). Previous studies in prostate and nonprostate cell lines have demonstrated that MSA exerted more powerful inhibitory effect on cell proliferation and viability than Se-Met and Se-(Methyl)selenocysteine (Ip et al, 2000;Dong et al, 2002;Venkateswaran et al, 2002;Zu and Ip, 2003). One potential explanation is that MSA delivers monomethylated selenium species directly to cells (Ip et al, 2000).…”

Nox5 and the Regulation of Cellular Function

“…Consumption of antioxidants such as lycopene has been associated with reduced prostate cancer risk (76), and scavenging of ROS with antioxidants increases prostate cancer survival in mice (78). However, the role of ROS and lycopene in prostate cancer is not without controversy (37).…”

Selenium and Vitamin E for Prostate Cancer: Post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) Status

“…Although limited by several factors including a small sample size and short duration of therapy, a recent study showed that the SELECT study agents, when given for 3-6 weeks before prostatectomy, created a greater overall difference in gene expression in tumor epithelial cells than administration of vitamin E or selenium alone, including specific increases in p53 gene transcription and translation (98). Using the male Lady version of the TRAMP mice, Venkateswaran et al (99) showed that ad-ministration of antioxidants (vitamin E, selenium and lycopene) in the diet dramatically inhibits PCa development and increases the disease-free survival. A strong correlation between disease-free state and increased levels of the prognostic marker p27(Kip1) and a marked decrease in proliferating cell nuclear antigen expression was also seen by the authors (99).…”

“…Using the male Lady version of the TRAMP mice, Venkateswaran et al (99) showed that ad-ministration of antioxidants (vitamin E, selenium and lycopene) in the diet dramatically inhibits PCa development and increases the disease-free survival. A strong correlation between disease-free state and increased levels of the prognostic marker p27(Kip1) and a marked decrease in proliferating cell nuclear antigen expression was also seen by the authors (99). However, a subsequent study by the same group suggested that lycopene is an essential component of the combination (100).…”