Oxidative Stress in Prostate Cancer

Changing Research Concepts Towards a Novel Paradigm for Prevention and Therapeutics

A Paschos; R Pandya; W C M Duivenvoorden; J H Pinthus

Disclosures

Prostate Cancer Prostatic Dis. 2013;16(3):217-225. 

In This Article

Antioxidative Treatment as Prevention Therapy

Modulating oxidative stress in PC cells is a conceivable means to control cancer progression. Although oxidative stress-mediated DNA damage is untreatable, chemicals that limit oxidative stress at the molecular level may reduce or deprive tumor cells of oxidative stress-induced signaling pathways and could potentially be useful to cause growth arrest. Despite intense investigations, clinical trials utilizing antioxidants have been disappointing, and no effective antioxidant agent is in widespread use. Epidemiological data for most cancer types suggest that consumption of foods that contain high levels of antioxidants might slow or prevent the appearance of cancer. β-Carotenes, lycopenes, vitamin E and selenium were and are considered dietary antioxidant molecules that aid in the physiological defense against oxidative stress. Numerous studies investigated antioxidants to verify their potential efficacy in the prevention and progression of PC. Table 2 lists notable PC prevention studies on dietary antioxidants. In 1998, the Finnish ABTC study looking at the prevention of lung cancer in a subgroup of smokers showed a statistically significant 32% reduction in PC incidence and 41% reduction in PC mortality in men receiving vitamin E (synthetic dl-α-tocopheryl acetate) (N=14 564) compared with controls (N=14 569). Although the study failed to achieve a competitive level of evidence, it has triggered a large interest in studying the effects of vitamin E and other antioxidants for the prevention of PC.

The largest and most definitive among these studies was the Selenium and Vitamin E Cancer Prevention Trial (SELECT) trial. Men aged ≥50 (black men only) or ≥55 years without clinical suspicion of PC, as defined by PSA ≤4 ng ml−1 and normal digital rectal exam, were randomized to one of four treatment groups; selenium alone (200 μg per day from L-selenomethionine; N=8752), vitamin E alone (400 IU per day of all rac-α-tocopheryl acetate; N=8737), both anti-oxidants (N=8702) or placebo (N=8696). The study showed that antioxidants fail to prevent, and in some cases may even promote, PC development. Vitamin E alone actually increases the risk of developing PC by 17% (P=0.008) when compared with placebo. When taken in combination with selenium, the risk of PC is not increased, and selenium alone does not protect against PC.[81] Several potential suggestions have been put forth to explain the results of the study, which were contrary to the original prevention hypothesis. (i) The high dose of vitamin E (400 IU), which was eight times higher than the 50 IU used in the ABTC study, may abolish the preventive effect or even contribute to the increased risk of PC demonstrated in the study.[82] (ii) Animal studies demonstrate cancer preventive activity of γ- and δ-tocopherols, as well as for the naturally occurring mixture of tocopherols, but not by α-tocopherol,[83] the source of vitamin E used in the SELECT trail. (iii) Different individuals may respond inconsistently to antioxidant treatment depending on specific, intrinsic genetic risk factors. In a very elegant study, Martinez et al.[84] demonstrated that in mice with mutated homeobox transcription factor Nkx3.1, which is frequently associated with human PC, antioxidant treatment actually increases prostatic epithelial cell proliferation and promotes the expression of a proproliferative gene signature, and more importantly, ROS does not promote proliferation in the prostate of Nkx3.1-null mice.[84] (iv) The chemoprevention protocol was not tailored to individuals. There was no baseline assessment of the prostatic oxidative status of the study participants before the start of the study. Different individuals have different profiles of oxidative stress, and one would expect minimal or no effect of antioxidative compounds in subjects with lower baseline oxidative stress.[29]

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