Review
β-Carotene: a cancer chemopreventive agent or a co-carcinogen?

https://doi.org/10.1016/S1383-5742(03)00002-4Get rights and content

Abstract

Evidence from both epidemiological and experimental observations have fueled the belief that the high consumption of fruits and vegetables rich in carotenoids may help prevent cancer and heart disease in humans. Because of its well-documented antioxidant and antigenotoxic properties, the carotenoid β-carotene (βCT) gained most of the attention in the early 1980s and became one of the most extensively studied cancer chemopreventive agents in population-based trials supported by the National Cancer Institute. However, the results of three randomized lung cancer chemoprevention trials on βCT supplementation unexpectedly contradicted the large body of epidemiological evidence relating to the potential benefits of dietary carotenoids. Not only did βCT show no benefit, it was associated with significant increases in lung cancer incidence, cardiovascular diseases, and total mortality. These findings aroused widespread scientific debate that is still ongoing. It also raised the suspicion that βCT may even possess co-carcinogenic properties. In this review, we summarize the current data on the co-carcinogenic properties of βCT that is attributed to its role in the induction of carcinogen metabolizing enzymes and the over-generation of oxidative stress. The data presented provide convincing evidence of the harmful properties of this compound if given alone to smokers, or to individuals exposed to environmental carcinogens, as a micronutrient supplement. This has now been directly verified in a medium-term cancer transformation bioassay. 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 data presented here point to the need for consideration of the possible detrimental effects of certain isolated dietary supplements, before mass cancer chemoprevention clinical trials are conducted on human subjects. This is especially important for genetically predisposed individuals who are environmentally or occupationally exposed to mutagens and carcinogens, such as those found in tobacco smoke and in industrial settings.

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 (1O2), 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.

References (54)

  • P. Perocco et al.

    β-Carotene as enhancer of cell transforming activity of powerful carcinogens and cigarette-smoke condensate on BALB/c 3T3 cells in vitro

    Mutat. Res.

    (1999)
  • P. Perocco et al.

    Inhibitory activity of Vitamin E and α-naphthoflavone on β-carotene-enhanced transformation of BALB/c 3T3 cells by benzo[a]pyrene and cigarette-smoke condensate

    Mutat. Res.

    (2000)
  • G.S. Ladics et al.

    Generation of 7,8-dihydroxy-9,10-tetrahydro-benzo[a]pyrene by murine splenic macrophages

    Toxicol. Appl. Pharmacol.

    (1992)
  • R.A. El-Zein et al.

    Polymorphism of metabolizing genes and lung cancer histology: prevalence of CYP2E1 in adenocarcinoma

    Cancer Lett.

    (1997)
  • S.Z. Abdel-Rahman et al.

    Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt

    Cancer Lett.

    (2000)
  • S.Z. Abdel-Rahman et al.

    The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK

    Cancer Lett.

    (2000)
  • D. Albanes et al.

    Effects of supplemental β-carotene, cigarette smoking, and alcohol consumption on serum carotenoids in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

    Am. J. Clin. Nutr.

    (1997)
  • C.S. Lieber et al.

    International Commission for Protection against Environmental Mutagens and Carcinogens, ICPEMC working paper no. 15/2, metabolism and metabolic effects of ethanol, including interaction with drugs, carcinogens and nutrition

    Mutat. Res.

    (1987)
  • M.A. Leo et al.

    Hepatotoxicity of Vitamin A and ethanol in the rat

    Gastroenterology

    (1982)
  • A.J. Gescher et al.

    Cancer chemoprevention by dietary constituents: a tale of failure and promise

    Lancet Oncol.

    (2001)
  • B.K. Edwards, H.L. Howe, L.A.G. Ries, M.J. Thun, H.M. Rosenberg, R. Yancik, P.A. Wingo, A. Jemal, E.G. Feigal, R.K....
  • W.C. Willett et al.

    Relation of serum Vitamins A and E and carotenoids to the risk of cancer

    New Engl. J. Med.

    (1984)
  • U. Saffiotti et al.

    Experimental cancer of the lung: inhibition by Vitamin A of the induction of tracheobronchial and squamous metaplasma and squamous cell tumors

    Cancer

    (1967)
  • R. Peto et al.

    Can dietary β-carotene materially reduce human cancer rates?

    Nature

    (1981)
  • The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group, The effect of Vitamin E and β-carotene on the...
  • D.O. Stram et al.

    Is residual confounding a reasonable explanation for the apparent protective effects of β-carotene found in epidemiologic studies of lung cancer in smokers?

    Am. J. Epidemiol.

    (2002)
  • G.S. Omenn et al.

    Risk factors for lung cancer and for intervention effects in CARET

    J. Natl. Cancer Inst.

    (1996)
  • Cited by (0)

    View full text