Vitamins C and E and Beta Carotene Supplementation and Cancer Risk: A Randomized Controlled Trial

Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Ave East, Boston, MA 02215, USA.
CancerSpectrum Knowledge Environment (Impact Factor: 15.16). 01/2009; 101(1):14-23. DOI: 10.1093/jnci/djn438
Source: PubMed

ABSTRACT Observational studies suggested that a diet high in fruits and vegetables, both of which are rich with antioxidants, may prevent cancer development. However, findings from randomized trials of the association between antioxidant use and cancer risk have been mostly negative.
From 8171 women who were randomly assigned in the Women's Antioxidant Cardiovascular Study, a double-blind, placebo-controlled 2 x 2 x 2 factorial trial of vitamin C (500 mg of ascorbic acid daily), natural-source vitamin E (600 IU of alpha-tocopherol every other day), and beta carotene (50 mg every other day), 7627 women who were free of cancer before random assignment were selected for this study. Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the National Death Index. Cox proportional hazards regression models were used to assess hazard ratios (represented as relative risks [RRs]) of common cancers associated with use of antioxidants, either individually or in combination. Subgroup analyses were conducted to determine if duration of use modified the association of supplement use with cancer risk. All statistical tests were two-sided.
During an average 9.4 years of treatment, 624 women developed incident invasive cancer and 176 women died from cancer. There were no statistically significant effects of use of any antioxidant on total cancer incidence. Compared with the placebo group, the RRs were 1.11 (95% confidence interval [CI] = 0.95 to 1.30) in the vitamin C group, 0.93 (95% CI = 0.79 to 1.09) in the vitamin E group, and 1.00 (95% CI = 0.85 to 1.17) in the beta carotene group. Similarly, no effects of these antioxidants were observed on cancer mortality. Compared with the placebo group, the RRs were 1.28 (95% CI = 0.95 to 1.73) in the vitamin C group, 0.87 (95% CI = 0.65 to 1.17) in the vitamin E group, and 0.84 (95% CI = 0.62 to 1.13) in the beta carotene group. Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death.
Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality.

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    • "Consequently, hypoxia stimulates a cascade of molecular pathways that affect angiogenesis, glycolysis and the metastasis of tumor cells [21] and targeting of the HIF-1α pathway is an appealing strategy for inhibiting cancer metastasis. β-Carotene (BC) is an active vitamin A precursor that is found in fruits and vegetables that are deep green or orange in color [22]. BC has also been found to reduce the incidence of epithelial cell cancers, which account for more than 90% of all cancer deaths [23]. "
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    • "In contrast to the studies in lower model organisms cited above, several prospective intervention trials did not find any health-promoting effects of antioxidant supplementation . Unexpectedly, most interventional studies found a lack of effects in humans (Greenberg et al. 1994, Liu et al. 1999, Rautalahti et al. 1999, Virtamo et al. 2000, Various 2002, Sacco et al. 2003, Zureik et al. 2004, Czernichow et al. 2005, Czernichow et al. 2006, Cook et al. 2007, Kataja- Tuomola et al. 2008, Sesso et al. 2008, Katsiki and Manes 2009, Lin et al. 2009, Song et al. 2009), whereas others even suggested detrimental effects on human health, for instance promotion of cancer growth or induction of diseases with negative impact on human lifespan (Albanes et al. 1996, Omenn et al. 1996, Vivekananthan et al. 2003, Lonn et al. 2005, Bjelakovic et al. 2007, Ward et al. 2007, Lippman et al. 2009, Schipper 2004, DeNicola et al. 2011, Abner et al. 2011). Consistently, several studies overexpressing antioxidant enzymes in mice failed to exert positive effects on lifespan or associated parameters (Jang et al. 2009, Muller et al. 2007, Perez et al. 2011). "
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    ABSTRACT: Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.
    Dose-Response 05/2014; 12(2):288-341. DOI:10.2203/dose-response.13-035.Ristow · 1.23 Impact Factor
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    • "Interestingly, data on beta-carotene supplements provide considerable evidence that high-dose supplements have a contrasting effect, at least in smokers, increasing the risk of lung cancer. Data on dietary beta-carotene (15 cohort studies, a pooled analysis, 32 case-control studies, 2 ecological studies) and serum or plasma beta-carotene (13 cohort studies, 16 case-control studies, 1 ecological study) showed no consistent evidence for association (Lin et al., 2009; Druesne-Pecollo et al., 2010; Jeon et al., 2011). "
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    ABSTRACT: It is well known that oxidative stress is an inevitable event in aerobic life. When our cells use oxygen to create energy, a variety of reactive oxygen (ROS) and nitrogen species (RNS) are generated. These species could attack DNA directly and form mutagenic lesions afterwards. According to the oxidative stress hypothesis of aging, the oxidative damage to critical molecules accumulates over the life period and could ultimately impair the body’s function. Moreover, severe oxidative stress causes mutations of tumor suppressor genes, known as one of the initial events in carcinogenesis. Furthermore, it could also play a crucial role in the promotion of the multi-step carcinogenesis. On the other hand, the human body possesses a number of mechanisms that counteract oxidative stress by producing antioxidants in situ, or externally supplied them through foods and/or supplements. Indeed, a considerable amount of laboratory evidence from chemical, cell culture, and animal studies indicates that antioxidants may slow down or possibly prevent the cancer development. Yet, the information from recent cohort, case-control and/or ecological studies is less clear. Therefore, the objectives of this review are to compile a compendium of studies, and to identify effective and promising natural antioxidant interventions.
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