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

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Mutation Research 543 (2003) 195–200


␤-Carotene: a cancer chemopreventive agent or a co-carcinogen? Moreno Paolini a , Sherif Z. Abdel-Rahman b , Andrea Sapone a , Gian Franco Pedulli c , Paolo Perocco d , Giorgio Cantelli-Forti a,b , Marvin S. Legator b,∗ a


Department of Pharmacology, Biochemical Toxicology Unit, University of Bologna, Via Irnerio 48, Italy Department of Preventive Medicine and Community Health, Division of Environmental Toxicology, 700 Harborside Drive, The University of Texas Medical Branch, Galveston, TX 77555-1110, USA c Department of Organic Chemistry “A. Mangini”, Via San Donato 15, Italy d Institute of Cancerology, Viale Filopanti 33, 40126 Bologna, Italy Received 8 October 2002; received in revised form 18 December 2002; accepted 18 December 2002

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 ␤-carotene (␤CT) 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 ␤CT supplementation unexpectedly contradicted the large body of epidemiological evidence relating to the potential benefits of dietary carotenoids. Not only did ␤CT 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 ␤CT may even possess co-carcinogenic properties. In this review, we summarize the current data on the co-carcinogenic properties of ␤CT 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. © 2003 Published by Elsevier Science B.V. Keywords: ␤-Carotene; Cancer; Chemopreventive agent

1. Introduction

∗ Corresponding author. Tel.: +1-409-772-1803; fax: +1-409-772-9108. E-mail address: [email protected] (M.S. Legator).

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

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M. Paolini et al. / Mutation Research 543 (2003) 195–200

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 multistep carcinogenic process. One group of such agents consists of naturally occurring dietary micronutrients and their related synthetic analogs. Because of the antioxidant properties of ␤-carotene (␤CT) 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 ␤CT can prevent cancer. By the early 1980s, there were a large number of epidemiological studies associating ␤CT 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 ␤CT. 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 ␤CT 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 ␤CT, 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 [5–8]. These findings strongly suggested that ␤CT 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].

2. Induction of cytochrome P450 and generation of oxidative stress by ␤-carotene ␤CT is effective in vitro in neutralizing singlet oxygen (1 O2 ), and, to a lesser extent, it is also effective in interrupting lipid peroxidation chain reactions. However, the na¨ıve 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, therefore, improbable that a single antioxidant agent could control or reduce the effects of such a complex cocktail of toxicants that act with many different mechanisms, and in antagonism or synergism with each other at various levels, to induce cancer. It has been suggested that ␤CT could stimulate progression of pre-existing latent tumors, rather than initiating new ones [12]. However, in some circumstances, ␤CT appears to act as an antigenotoxic agent [13–15]. Because of these conflicting reports, a recent investigation was conducted to determine whether ␤CT might act by means of epigenetic, or co-carcinogenic mechanisms. These could involve changes in metabolizing enzymes, such as cytochrome P450 (CYP) isoforms [16]. In an animal model, ␤CT supplementation produced a powerful booster effect on phase I carcinogen bioactivating enzymes in the lung. These phase I enzymes include the cytochrome P450s CYP1A1, CYP1A2 (activating aromatic amines, polychlorinated biphenyls, dioxins, polycyclic aromatic hydrocarbons (PAHs)), CYP3A (aflatoxins, 1-nitropyrene, PAHs), CYP2B1 (olefins, halogenated hydrocarbons) and CYP2A (butadiene, phosphoramide, and nitrosamines). Furthermore, this induction was found to be associated with the generation of oxidative stress [17]. This phenomenon was also observed in liver, kidney and intestine [18]. Many of these potentially carcinogenic chemicals could also act synergistically with ␤CT as CYP inducers to impose an even greater co-carcinogenic effect.

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Interestingly, ferrets given high ␤CT supplements and then exposed to tobacco smoke have diminished retinoid signaling, resulting from the suppression of retinoic acid receptor ␤ gene expression, and from over-expression of activator protein-1 [19]. Increased bioactivation of pro-carcinogens to final carcinogens could also facilitate lung tumorigenesis by saturating DNA repair mechanisms and altering tumor suppressor genes [17]. If the same response occurs in humans, this could predispose individuals who are occupationally or environmentally exposed to mutagens and carcinogens to higher cancer risk from bioactivated pro-carcinogens [17]. This effect may become even more pronounced in genetically predisposed individuals who have inherited “high risk” genotypes affecting metabolic and DNA repair enzymes [20]. The existence of NADPH-dependent production of reactive oxygen species (ROS) such as O2 •− , HO• or H2 O2 by animal liver microsomes, linked to uncoupling of electron transfer and oxygen reduction by specific CYPs [21], has been known for over 40 years [22]. In 1996, however, it was demonstrated that this is a general phenomenon involving all the major CYP subfamilies of isoenzymes [23]. This effect was confirmed by a recent study reporting NADPH-stimulated release of ROS by subcellular preparations enriched with specific human CYPs [24]. These observations are consistent with the concept that, while functioning as an antioxidant, ␤CT may indeed act as an anticarcinogen, whereas its oxidized products, which are particularly high in smokers, can at the same time facilitate carcinogenesis [25]. It thus seems reasonable to assume that any induction of CYPs caused by ␤CT supplementation could contribute to the observed ROS increase [17]. In smokers ROS over-generation may, acting together with other chemicals in cigarette smoke, reduce the levels of unoxidized ␤CT (i.e. the protective form of the provitamin), thus expanding the mixture of oxidation products [26]. In smokers, the oxidative stress, stemming from CYP up-regulation per se, could also act synergistically with the many oxidants contained in cigarette smoke, such as nitrogen dioxide, hydroquinones and peroxyl radicals [27,28]. This could induce even more genetic damage and, accordingly, impose higher cancer risk. ␤CT must, therefore, be considered an “unusual” antioxidant because it has been unambiguously demonstrated that, while it behaves as an antioxi-


dant at oxygen partial pressures that are significantly lower than the oxygen pressure found in normal air, at higher oxygen pressures it actually behaves as a pro-oxidant [29]. This phenomenon, observed in the presence of ␤CT, and reproduced in purified systems [30], microsomes [25], cell lines [31], and bacteria [32], should not be underestimated, since cells lining the outer surface of the lung are exposed to considerably higher oxygen partial pressure than other tissues. 3. The co-carcinogenicity of ␤-carotene enhances the transformation potential of benzo[a]pyrene and cigarette-smoke condensate In an effort to directly verify the co-carcinogenic properties of ␤CT, 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 ␤CT 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 ␤CT, when tested alone, did not exert any cell transforming activity (induction of transformed cell foci), it markedly increased the cell transforming potential of the tested agents. In the absence of any direct effect on DNA, it was hypothesized that the observed increase of cell transformation foci could be explained by the co-carcinogenic properties of ␤CT. In other words, the observed increase in cell transformation could be due to either CYP induction or ROS overproduction occurring during cell growth. Cigarette-smoke condensate also induced cell-transforming activity in the BALB/c 3T3 model, particularly after prolonged ␤CT exposure [35]. These observations provide a logical explanation for the increased incidence of lung tumors in subjects receiving ␤CT supplements who were also heavy smokers [5,7,8,36]. Interestingly, the concentration of ␤CT used in the medium-term bioassay studies (1 ␮M, i.e. 0.5 ␮g/ml) was comparable to the concentration of ␤CT found in the plasma (2–3 ␮g/ml) of individuals enrolled in the ␤CT supplementation program who received a daily dose of 20–30 mg of ␤CT [37]. The hypothesis that ␤CT has co-carcinogenic properties is further supported by a recent study indicating that blocking either CYP up-regulation or ROS


M. Paolini et al. / Mutation Research 543 (2003) 195–200

overproduction deprives ␤CT of its detrimental properties [38]. Indeed, when BALB/c 3T3 cells were treated with B[a]P or cigarette-smoke condensate in the presence of either ␣-naphthoflavone (a typical inhibitor of the CYP that activates PAHs) or ␣-tocopherol (a free-radical scavenger), a significant protective effect was observed in the presence of ␤CT [38]. This phenomenon was attributed to the reduced formation of B[a]P metabolites, such as the powerful carcinogen B[a]P-7,8-diol-9,10-epoxide, as well as phenols, diols, quinones and oxyradical products, all of which possess various mutagenic and carcinogenic properties [23,24,39–41]. In the presence of occupational or environmental exposure to mutagens and carcinogens, the high levels of CYP induced by ␤CT supplementation could predispose individuals to higher cancer risk due to increased bioactivation of pro-carcinogens, as well as increased production of ROS (the co-carcinogenic effect) [17]. This effect could be further enhanced in subjects who possess predisposing susceptibility factors, such as polymorphisms in genes involved in the bioactivation and the detoxication of carcinogens [20,42,43] and the repair of the resulting genetic damage [44,45]. In the absence of adequate detoxication capacity and the lack of efficient DNA repair, increased bioactivation of pro-carcinogens to ultimate carcinogens could facilitate tumorigenesis by saturating DNA repair mechanisms. It is interesting to note that a number of the subjects who developed lung cancer in the ATBC and CARET trials were also heavy consumers of alcohol [46], a known inducer of carcinogen metabolizing enzymes [47]. It has been reported that Vitamin A and/or ␤CT could also enhance the hepatotoxicity of ethanol [48]. Thus, both alcohol and ␤CT may act synergistically to induce CYP isoforms [49] and enhance the carcinogenic effect of smoking.

4. Conclusions In summary, the data presented here suggest that ␤CT 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 ␤CT case offers an exemplary warning for the need to consider the possible detrimental effects of isolated dietary supplements before mass cancer chemoprevention clinical trials are conducted. This is especially true in individuals exposed to environmental mutagens and carcinogens such as those found in tobacco smoke and industrial settings. Furthermore, it provides an example of the pitfalls that can occur if simplistic attempts are made to reproduce the benefits of a varied plant-based diet (containing thousands of substances in a natural matrix) by means of consumption of a single nutrient such as a provitamin or vitamin [50,51]. The ␤CT story, in addition to dampening some premature enthusiasms, suggests an important prerequisite that should be fulfilled before large clinical trials are undertaken with human subjects. In addition to mechanistic investigations, rigorous overall toxicological characterization of the selected chemopreventive agent is needed, using both in vitro and in vivo models with toxicological end-points [10,52]. Also, the “genetic homogeneity and make-up” of the trial population with respect to the DNA repair capacity and ability to activate or detoxify carcinogens should be considered. For example, individuals exposed to chemical carcinogens either environmentally or occupationally, who possess predisposing susceptibility factors, such as polymorphisms in genes involved in the bioactivation and the detoxication of carcinogens [20,42,43,53,54] and the repair of the resulting genetic damage [44,45] may be more susceptible than others. This could significantly confound the interpretation of the results of a clinical trial [53]. In the meantime, the high fruit and vegetable intake recommendations, from both the public health agencies and the scientific community as a whole, should continue to be encouraged. As argued above, there are strong scientific reasons to suspect that the concept that cancer chemoprevention can be based solely on the selective administration of one or more isolated dietary supplements may be na¨ıve.

Acknowledgements This work was supported by a Ministry of Instruction, University and Research of Italy (MIUR) grant

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