Abstract
A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men.
Highlights
Prostate cancer is the most common human malignancy and the second leading cause of cancer death among men in western nations
These results suggested that vitamin E enhances the bioactivating potential of the cytochrome P-450 (CYP) supergene family, making prostate cells more vulnerable to exposure to pro-mutagenic and pro-carcinogenic agents
Vitamin E plays a critical role in impairing redox homeostasis, while the pro-inflammatory cyclooxygenase-2 (COX-2) prostaglandin-2 (PGE2) pathway is involved in various malignancies, including prostate cancer[21,22], by means of resistance to apoptosis, increased proliferation, invasiveness, metastasis and angiogenesis
Summary
Prostate cancer is the most common human malignancy and the second leading cause of cancer death among men in western nations. Supported by preclinical and epidemiological evidence, antioxidants from food and supplements are widely used to protect against cancer, but clinical trials do not sustain this concept[1,3,4,5,6] and showed a higher incidence of prostate cancer[7,8]. Conceived to break through this issue, in 2001 the National Cancer Institute (NCI) launched SELECT (Selenium and vitamin E Cancer Prevention Trial), that showed a 17% increase in prostate cancer incidence in the vitamin E arm compared to placebo[7]. Since some cytochrome P-450 (CYP) isoforms have been found overexpressed in prostate cancer[10,11,12,13,14,15], we suspected that vitamin E could have co-carcinogenic properties such as those involving carcinogen-bioactivating CYP-enzyme changes[16,17]
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