Reviewβ-Carotene: a cancer chemopreventive agent or a co-carcinogen?
Introduction
Despite the encouraging decrease in the prevalence of tobacco smoking in industrialized western countries, lung cancer remains the leading cause of cancer death in both women and men, and is rapidly increasing in the developing world [1]. The realization that tobacco abuse cannot be rapidly eliminated worldwide, the disappointing results of early detection efforts to control lung cancer, and the high rates of recurrence following treatment, all point to the paramount need for chemopreventive approaches to control this disease. An approach to chemoprevention that has gained great appeal involves the use of specific agents capable of inhibiting or reversing the multi-step carcinogenic process. One group of such agents consists of naturally occurring dietary micronutrients and their related synthetic analogs. Because of the antioxidant properties of β-carotene (βCT) and other carotenoids, these substances have attracted a great deal of attention over the past two decades as potential chemopreventive agents. Early epidemiological and animal studies [2], [3] advanced the idea that βCT can prevent cancer. By the early 1980s, there were a large number of epidemiological studies associating βCT intake with lower incidence of epithelial cancers, particularly lung cancer. In 1981 Peto et al. [4] summarized the results of prospective and retrospective case–control questionnaire-based studies of populations in eight different countries and provided sufficient evidence of the potential cancer-preventive benefits of βCT. This in turn led to several randomized trials designed to test the hypothesis in human populations.
Unexpectedly, however, the results of three recent randomized clinical trials of βCT supplementation for the prevention of lung cancer among smokers contradicted the large body of epidemiological evidence [5], [6]. Indeed, chemoprevention trials such as the Alpha-Tocopherol, Beta-Carotene Trial (ATBC) and the Carotene and Retinol Efficacy Trial (CARET) showed that βCT, either alone or in combination with Vitamins A or E, could actually increase lung cancer incidence and mortality in heavy smokers and in asbestos workers [5], [6], [7], [8]. These findings strongly suggested that βCT might possess co-carcinogenic properties. More recently, the long-awaited results from the European Study on Chemoprevention with Vitamin A and N-acetylcysteine (EUROSCAN), and the randomized two-by-two factorial trial of retinyl palmitate and N-acetylcysteine in patients with treated cancer of the lung or the head and neck, showed no benefit from these chemicals, whether taken singly or in combination [9]. Based on these studies, it was correctly argued that the results of these trials emphasize the importance of developing a solid scientific basis, from both in vitro and in vivo mechanistic studies, to guide the selection and development of potentially effective chemopreventive agents and to justify their use in trials involving human subjects [10].
Section snippets
Induction of cytochrome P450 and generation of oxidative stress by β-carotene
βCT is effective in vitro in neutralizing singlet oxygen (), and, to a lesser extent, it is also effective in interrupting lipid peroxidation chain reactions. However, the naı̈ve belief that this radical-trapping ability can decrease the incidence of lung cancer in humans seems rather simplistic. Tobacco smoke is a very complex mixture containing thousands of substances, at least 40 of which have been identified as carcinogens or tumor promoters in laboratory animals [11]. It seems,
The co-carcinogenicity of β-carotene enhances the transformation potential of benzo[a]pyrene and cigarette-smoke condensate
In an effort to directly verify the co-carcinogenic properties of βCT, a medium-term bioassay (6–8 weeks) with BALB/c 3T3 cells, which correlates well (70–85%) with in vivo carcinogenesis, was used [33], [34]. The results of these studies show that βCT was able to markedly enhance the conversion of both 3-methylcholanthrene and the procarcinogen benzo[a]pyrene (B[a]P) to ultimate carcinogens [35]. While βCT, when tested alone, did not exert any cell transforming activity (induction of
Conclusions
In summary, the data presented here suggest that βCT may act as a co-carcinogen through different mechanisms. These mechanisms involve the induction of CYPs leading to increased bioactivation of procarcinogens and/or increasing the levels of ROS, thereby increasing the risk for tumorigenesis. In the context of public health policies, while the benefits of a diet rich in a variety of fruits and vegetables should continue to be emphasized, the βCT case offers an exemplary warning for the need to
Acknowledgements
This work was supported by a Ministry of Instruction, University and Research of Italy (MIUR) grant and, in part, by Philip Morris Inc. We are grateful to Dr. Marinel M. Ammenheuser and Robin M.T. Cooke for editing.
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