Anticarcinogenic Activity

Observational epidemiological studies have consistently shown a relationship between dietary beta-carotene intake and low risk of various cancers (Cooper et al 1999b, Pryor et al 2000). In animal studies beta-carotene has been found to be chemoprotective, with inhibition of spontaneous mammary tumours (Fujii et al 1993, Nagasawa et al 1991), as well as prevention of skin carcinoma formation (Ponnamperuma et al 2000), UV-induced carcinogenesis in mice (Epstein 1977, Mathews-Roth 1982) and oral cancer in laboratory and animal models (Garewal 1995). Studies in ferrets suggest that the beta-carotene molecule becomes unstable in smoke-exposed lungs and that when given with alpha-tocopherol and ascorbic acid to stabilise the beta-carotene molecule, there is a protective effect against smoke-induced lung squamous metaplasia (Russell 2002).

A review of carotenoid research by the International Agency for Research on Cancer suggests there is sufficient evidence that beta-carotene has cancer-preventive activity in experimental animals, based on models of skin carcinogenesis in mice and buccal pouch carcinogenesis in hamsters (Vainio & Rautalahti 1998), despite a review suggesting that beta-carotene does not protect against lung cancer in animals (De Luca & Ross 1996).

Whether beta-carotene has anticancer properties in humans is unclear. It has been suggested any such effects could be mediated through multiple mechanisms that may include antioxidant activity preventing oxidative damage to DNA and inhibition of lipid peroxidation, stimulation of gap junction communication, effects on cell transformation and differentiation, inhibition of cell proliferation and oncogene expression, effects on immune function and inhibition of endogenous formation of

carcinogens (Cooper et al 1999). Additional mechanisms may include the metabolic conversion of beta-carotene to retinoids, which may in turn modulate the gene expression of factors linked to differentiation and cell proliferation. The modulation of enzymes that metabolise xenobiotics and inhibition of endogenous cholesterol synthesis by modulation of HMG-CoA reductase expression may also lead to a possible inhibition of cell proliferation and malignant transformation (PDRHealth 2005).

None of these mechanisms has been conclusively found to contribute to preventing cancer in vivo and there is ongoing debate as to the role of beta-carotene in cancer prevention (Cooper et al 1999, Patrick 2000). This debate has been further fuelled by the findings of two large intervention studies, the Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Prevention Study (the 'Finnish study'; Heinonen et al 1994) and the Carotene and Retinol Efficacy Trial (CARET; Omenn et al 1996a), which found a significantly increased risk of lung cancer in high-risk individuals supplemented with synthetic beta-carotene (see Clinical Use for more details).

The mixed findings from beta-carotene intervention trials has produced much controversy in the scientific literature and although it has been suggested that there is no known biologically plausible explanation for the finding, a number of hypotheses have been put forward (Bendich 2004).

It has been suggested that the dose, duration of study and/or choice of synthetic a\\-trans- beta-carotene may have been inappropriate to use in the intervention trials (Cooper et al 1999) and that supplementation with monotherapy using synthetic beta-carotene may have inhibited the absorption of other carotenoids (Woodall et al 1996). It is also suggested that, although beta-carotene may be effective in the prevention of lung cancer before or during the phases of initiation and early promotion of cancer, the intervention studies that involved heavy smokers and asbestos workers probably included individuals in whom these processes were already initiated (Bendich 2004).

Additional possible explanations for the observed increase in lung cancer risk with beta-carotene supplementation include possible pro-oxidant activity of beta-carotene or its oxidative metabolites in the high oxygen environment of smokers' lungs, with oxidised beta-carotene metabolites inducing carcinogen-bioactivating enzymes, facilitating the binding of metabolites to DNA, enhancing retinoic acid metabolism by P450 enzyme induction and acting as pro-oxidants, causing damage to DNA (Russell 2002), as well as inhibition of retinoid signalling (Wang et al 1999). It is further suggested that the beta-carotene molecule may become unstable due to a low level of antioxidants, such as ascorbic acid, being present in smokers compared with nonĀ© 2007 Elsevier Australia

smokers (Bohm et al 1997), together with significant oxidative stress also being in present in smokers who consume high amounts of alcohol (PDRHealth 2005).

It has further been suggested that beta-carotene may increase lung cancer risk in smokers because of its ability to improve lung function. Thus smokers supplemented with beta-carotene may have increased lung capacity, resulting in deeper breathing of carcinogens and other oxidants. It is also suggested that beta-carotene may improve smokers' immune responses and thus reduce the number of days they suffered from upper respiratory tract infections and enabling them to smoke more (Bendich 2004).

The suggestion that beta-carotene may have pro-oxidant effects is supported by an in vitro study showing that although cell viability and DNA integrity was not affected by beta-carotene, it was significantly and dose-dependently decreased by oxidised beta-carotene (Yeh & Hu 2001). There was a dose-dependent increase of beta-carotene cleavage products, together with increasing genotoxicity in vitro when beta-carotene was supplemented during oxidative stress induced by hypoxia/reoxygenation (Alija et al 2004, 2005). Carotenoid cleavage products have also been found to impair mitochondrial function and increase oxidative stress in vitro (Siems et al 2002, 2005), as well as produce a booster effect on phase I carcinogen-bioactivating enzymes in the rat lung (Paolini et al 1999). Beta-carotene has also been shown to be degraded by stimulated polymorphonuclear leukocytes in vitro, producing highly reactive and potentially toxic cleavage products (Sommerburg et al 2003). These pro-oxidant effects have not been conclusively demonstrated in vivo and beta-carotene at a dose of 50 mg/day for several years was not found to have pro-oxidant effects in either smokers or non-smokers, as measured by urinary excretion of F2-isoprostanes (Mayne et al 2004).

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