Skip to main content Accessibility help
×
Home
Hostname: page-component-559fc8cf4f-s65px Total loading time: 6.508 Render date: 2021-03-06T01:50:21.518Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": false, "newCiteModal": false, "newCitedByModal": true }

Phytochemicals and cancer

Published online by Cambridge University Press:  30 April 2007

Ian T. Johnson
Affiliation:
Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
Corresponding
E-mail address:
Rights & Permissions[Opens in a new window]

Abstract

Epidemiological studies showing a protective effect of diets rich in fruits and vegetables against cancer have focused attention on the possibility that biologically-active plant secondary metabolites exert anti-carcinogenic activity. This huge group of compounds, now collectively termed ‘phytochemicals’, provides much of the flavour and colour of edible plants and the beverages derived from them. Many of these compounds also exert anti-carcinogenic effects in animal models of cancer, and much progress has been made in defining their many biological activities at the molecular level. Such mechanisms include the detoxification and enhanced excretion of carcinogens, the suppression of inflammatory processes such as cyclooxygenase-2 expression, inhibition of mitosis and the induction of apoptosis at various stages in the progression and promotion of cancer. However, much of the research on phytochemicals has been conducted in vitro, with little regard to the bioavailability and metabolism of the compounds studied. Many phytochemicals present in plant foods are poorly absorbed by human subjects, and this fraction usually undergoes metabolism and rapid excretion. Some compounds that do exert anti-carcinogenic effects at realistic doses may contribute to the putative benefits of plant foods such as berries, brassica vegetables and tea, but further research with human subjects is required to fully confirm and quantify such benefits. Chemoprevention using pharmacological doses of isolated compounds, or the development of ‘customised’ vegetables, may prove valuable but such strategies require a full risk–benefit analysis based on a thorough understanding of the long-term biological effects of what are often surprisingly active compounds.

Type
Research Article
Copyright
Copyright © The Author 2007

Abbreviations:
COX

cyclooxygenase

GST

glutathione S-transferase

ITC

isothiocyanate

NNK

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

A review by the author and colleagues was published in 1994 (Johnson et al. Reference Johnson, Williamson and Musk1994) that explored the potential anti-carcinogenic effects of a range of biologically-active secondary plant metabolites commonly present in human diets, and tentatively considered whether such compounds, now commonly referred to collectively as ‘phytochemicals’, might usefully be regarded as a new class of micronutrients. The interest in these compounds was stimulated partly by the work of pioneers in this field such as Wattenberg (Reference Wattenberg1975a,Reference Wattenbergb), who first demonstrated the principles of chemoprevention by plant constituents in animal models, and partly by the wealth of epidemiological evidence then emerging for protective effects of diets rich in fruits and vegetables against a variety of cancers (Block et al. Reference Block, Patterson and Subar1992). A great deal of new evidence has become available in the last decade, and awareness of the importance of plant foods in the prevention of chronic disease in general has grown apace (Daviglus et al. Reference Daviglus, Liu, Pirzada, Yan, Garside and Wang2005; Houston et al. Reference Houston, Stevens, Cai and Haines2005; He et al. Reference He, Nowson and MacGregor2006). The aim of the present paper is to review some important aspects of emerging knowledge about the anti-carcinogenic effects of plant secondary metabolites at the cellular and molecular levels, and to reappraise the overall importance of these compounds and their metabolites in human nutrition. To begin with, however, it will be useful to consider briefly the most recent epidemiological evidence for anti-carcinogenic effects of fruits and vegetables.

Cancer, plant foods and human diets

Much of the earliest evidence for protective effects of fruits and vegetables against cancer was based on case–control studies. In an important review Block and colleagues (Block et al. Reference Block, Patterson and Subar1992) summarised the available evidence and showed that after controlling for confounding factors, individuals in the lowest population quartile for fruit and vegetable intake experience about twice the risk of cancer compared with those in the highest quartile. A few years later Steinmetz & Potter (Reference Steinmetz and Potter1996) came to a similar conclusion, and the World Cancer Research Fund (1997) major study, Food, Nutrition and the Prevention of Cancer, found ‘convincing’ evidence for protective effects of fruits and vegetables against cancers of the upper aerophagic tract, stomach and lung, and of vegetables against cancers of the colon and rectum. Since the turn of the millennium, however, there appears to have been a shift in opinion toward the view that the evidence is less strong than originally thought, mainly because several large prospective studies focusing on the main causes of cancer in Western countries have found either no protective effects (Michels et al. Reference Michels, Edward, Joshipura, Rosner, Stampfer, Fuchs, Colditz, Speizer and Willett2000; Smith-Warner et al. Reference Smith-Warner, Spiegelman, Yaun, Adami, Beeson and van den Brandt2001) or weaker effects than those expected on the basis of previous case–control studies (Terry et al. Reference Terry, Terry and Wolk2001; Smith-Warner et al. Reference Smith-Warner, Spiegelman, Yaun, Albanes, Beeson and van den Brandt2003). The recent publication of results on breast and prostate cancer derived from the European Prospective Investigation into Cancer and Nutrition (Key et al. Reference Key, Allen, Appleby, Overvad, Tjonneland and Miller2004; van Gils et al. Reference van Gils, Peeters, Bueno-de-Mesquita, Boshuizen, Lahmann and Clavel-Chapelon2005) suggests that this trend is continuing.

The most comprehensive summary of the field currently available is probably that of the International Agency for Research on Cancer (2003), which has concluded that: ‘There is limited evidence for a cancer-preventive effect of consumption of fruit and of vegetables for cancers of the mouth and pharynx, oesophagus, stomach, colon-rectum, larynx, lung, ovary (vegetables only), bladder (fruit only) and kidney. There is inadequate evidence for a cancer-preventive effect of consumption of fruit and vegetables for all other sites’. Nevertheless, although both the perceived size and statistical significance of the anti-carcinogenic effects of diets rich in fruits and vegetables have diminished with the passage of time, interest in the biological effects of their constituents has grown. The emerging evidence for a variety of potentially-important anti-carcinogenic mechanisms has stimulated interest in the broad concept of chemoprevention, focused attention on particular fruits and vegetables rich in the most active compounds and encouraged a more mechanistic approach to epidemiology. Some of these issues will be discussed after the molecular effects of particular groups of phytochemicals have been reviewed.

Blocking tumour initiation

Studies of the anti-carcinogenic effects of a variety of plants, plant constituents and synthetic chemopreventive agents led Wattenberg (Reference Wattenberg1985) to define food-borne anti-carcinogens generally as either blocking agents, which act immediately before or during the initiation of carcinogenesis by chemical carcinogens, or suppressing agents, which act after initiation during the prolonged stages of promotion and progression. This framework has been valuable for the development of research on the many different types of secondary plant metabolites that show biological activity in mammals (Johnson et al. Reference Johnson, Williamson and Musk1994), and it continues to provide a valuable approach to the classification of these compounds and their effects. A scheme for the interactions between blocking agents, suppressing agents and the generalised sequence for the onset of neoplasia is shown in Fig. 1.

Fig. 1. A general scheme for interactions occurring between blocking agents and suppressing agents and the various stages in the sequence of events associated with the stepwise development of neoplasia. Blocking agents act immediately before or during the initiation of carcinogenesis by chemical carcinogens, and suppressing agents act after initiation, during the prolonged stages of promotion and progression. (Adapted from Johnson et al. Reference Johnson, Williamson and Musk1994.)

Modulation of carcinogen metabolism

Blocking agents prevent genotoxic carcinogens from forming adducts with DNA, either by inhibiting their activation from procarcinogens or by enhancing their detoxification and excretion. These actions are thought to be achieved primarily through the modulation of phase I and phase II metabolic enzymes in the gut, liver and other tissues exposed to the environment. Phase I metabolism involves the oxidation, reduction and hydrolysis of xenobiotics, including drugs, toxins and carcinogens, principally by the cytochrome P450 enzymes (Nelson et al. Reference Nelson, Kamataki, Waxman, Guengerich, Estabrook and Feyereisen1993). The products of phase I metabolism are often highly-reactive genotoxic intermediates that form substrates for phase II enzymes such as glutathione S-transferase (GST), NAD:quinone reductase and γ-glutamylcysteine synthetase, which then catalyse the formation of less-reactive water-soluble conjugates. These conjugates are then readily excreted via the kidneys or in bile. Certain anti-carcinogenic phytochemicals induce transcriptional activation of phase I and II enzymes, via the xenobiotic response element and the antioxidant response element respectively. The so-called monofunctional inducers are those that interact primarily with the antioxidant response element, and hence selectively induce phase II enzymes, without simultaneously inducing activation of carcinogens via increased phase I activity (Prochaska & Talalay, Reference Prochaska and Talalay1988). The mechanism of induction is thought to be triggered by cellular stress, which leads to activation of intracellular protein kinases favouring the translocation of the transcription factor NF-E2 p45-related factor-2 to the nucleus, where it binds to the antioxidant response element and up regulates transcription (Itoh et al. Reference Itoh, Chiba, Takahashi, Ishii, Igarashi and Katoh1997). Recent findings have shown that a second transcription factor, the aryl hydrocarbon receptor, interacts directly with the NF-E2 p45-related factor-2 promoter, and that this functional link contributes to the coupling of phase I and II enzymes as an integrated system (Miao et al. Reference Miao, Hu, Scrivens and Batist2005).

Several groups of phytochemicals have now been identified as potent inducers of phase II enzymes; two of the most actively investigated are the flavanols, including epigallocatechin gallate, which is the principal biologically-active component of green tea (Chou et al. Reference Chou, Chu, Hsu, Chiang and Wang2000), and the glucosinolate breakdown products, derived from cruciferous vegetables and herbs. Glucosinolates, of which >100 have been identified, are water-soluble glycosides containing a common S moiety and a variable side chain. They are found in cruciferous plants, a large and diverse group that contains mustard (Brassica juncea), rocket (Eruca sativa), radishes (Raphanus sativus) and the brassica vegetables (Mithen et al. Reference Mithen, Dekker, Verkerk, Rabot and Johnson2000). Intact glucosinolates are biologically inactive and remain sequestered within cells throughout the plant. However, when the raw tissues are mechanically disrupted, the glucosinolates come into contact with the endogenous enzyme myrosinase and undergo hydrolysis, yielding an unstable intermediate that can give rise to a variety of active products (Mithen et al. Reference Mithen, Dekker, Verkerk, Rabot and Johnson2000). Depending on the structure of the parent glucosinolate and the ambient conditions, these active products include isothiocyanates (ITC), nitriles, cyano-epithioalkanes and thiocyanates (Lambrix et al. Reference Lambrix, Reichelt, Mitchell-Olds, Kliebenstein and Gershenzon2001). In addition, the indolyl glucosinolates give rise to the indole-3-carbinols, which also induce detoxifying enzymes and act as anti-carcinogens in animal models (McDanell et al. Reference McDanell, McLean, Hanley, Heaney and Fenwick1988). Glucosinolate breakdown products can be formed in food processing, during digestion of uncooked vegetables in the upper gastrointestinal tract (Rouzaud et al. Reference Rouzaud, Young and Duncan2004) and by exposure to bacterial myrosinase in the colon (Rouzaud et al. Reference Rouzaud, Rabot, Ratcliffe and Duncan2003). Fig. 2 illustrates the release of glucosinolates in the gut lumen, the uptake and metabolism of the isothiocyanates and some possible sites of action and routes of excretion. The ITC sulforaphane, derived from broccoli (Brassica oleracea), acts via the NF-E2 p45-related factor-2 pathway (McWalter et al. Reference McWalter, Higgins, McLellan, Henderson, Song, Thornalley, Itoh, Yamamoto and Hayes2004) and is amongst the most active food-borne monofunctional inducers yet identified (Talalay & Fahey, Reference Talalay and Fahey2001).

Fig. 2. Glucosinolates are broken down by myrosinase during food processing or during digestion, and isothiocyanates and other breakdown products are released into the lumen. Some remain unabsorbed and are eventually broken down by the gut microflora, but a substantial quantity of free isothiocyanates diffuse passively into the mucosal epithelial cells where they are rapidly conjugated with glutathione (GSH), and then partially secreted back into the gut lumen by P-glycoprotein (Pgp-1) and multi-drug-resistance protein (MRP-1). Some free and conjugated isothiocyanates enter the bloodstream, however, and become available to interact with target tissues before further metabolism and urinary excretion. GST, glutathione S-transferase.

A considerable amount of work has also been done to explore the importance of these effects at the whole organism level by studying carcinogen metabolism in animal models and in human subjects exposed to carcinogens from cigarette smoke. Both indole-3-carbinol and phenethyl ITC have been shown to modify the metabolism of the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rodent models and inhibit the development of lung tumours, although their mechanisms of action differ. Indole-3-carbinol induces hepatic α-hydroxylation of NNK, thus reducing the delivery of NNK to the lung (Morse et al. Reference Morse, LaGreca, Amin and Chung1990), whereas phenethyl ITC inhibits α-hydroxylation, and hence adduct formation in lung tissue (Hecht et al. Reference Hecht, Trushin, Rigotty, Carmella, Borukhova, Akerkar and Rivenson1996). The shunting of NNK metabolism away from the lung leads to increased hepatic metabolism and higher urinary excretion of NNK metabolites. Increased urinary excretion of two such metabolites, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and [4-(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-β-ώ-d-glucosiduronic acid in human smokers consuming approximately 170 g watercress (Rorippa nasturtium-aquaticum)/d for 3 d suggests that a similar mechanism occurs in human subjects (Hecht et al. Reference Hecht, Chung, Richie, Akerkar, Borukhova, Skowronski and Carmella1995). Hecht and co-workers (Hecht et al. Reference Hecht, Carmella, Kenney, Low, Arakawa and Yu2004) have recently conducted a study of NNK metabolites in Singapore Chinese smokers and have reported an inverse correlation between cruciferous vegetable consumption and excretion of NNK metabolites that appears consistent with the known metabolic effects of indole-3-carbinol. Overall, the experimental and epidemiological evidence supports the conclusion that glucosinolate breakdown products modulate phase II metabolism in man, although the contribution of this mechanism to the putative anti-carcinogenic effects of cruciferous vegetable consumption remains to be fully established.

Suppressing tumour progression

Once the critical genetic damage has occurred, the next stages in the development of neoplasia are the acquisition of further mutations and epigenetic marks that cause progressively abnormal gene expression. This progression is the promotion stage of cancer development, characterised by poorly-regulated cell proliferation and differentiation, and a reduced tendency for damaged cells to undergo apoptosis. Eventually, the cancer phenotype emerges at one or more discrete sites. There are many stages at which this complex process might, in principle, be slowed or interrupted, and a correspondingly large number of plausible mechanisms for tumour suppression. Chemoprevention, the use of drugs or natural compounds at pharmacological levels to inhibit the development of cancer, is currently attracting a great deal of interest, particularly in the USA, but many of the same mechanisms may be triggered by phytochemicals occurring in substantial quantities in human diets.

Inflammation and cancer

It has long been recognised that inflammation is a risk factor for certain cancers (Balkwill & Mantovani, Reference Balkwill and Mantovani2001). One obvious example is the increased risk of colo-rectal cancer associated with inflammatory bowel disease (Ekbom et al. Reference Ekbom, Helmick, Zack and Adami1990), but there are other examples of the involvement of inflammatory processes in the initiation and progress of cancer both within (Macarthur et al. Reference Macarthur, Hold and El-Omar2004) and beyond the alimentary tract (Askling et al. Reference Askling, Grunewald, Eklund, Hillerdal and Ekbom1999). There is also circumstantial evidence that chronic systemic inflammation, associated perhaps with the adverse metabolic factors now so common in prosperous Westernised societies (Johnson, Reference Johnson2005), may be a key driver for cancers of the alimentary tract (Helzlsouer et al. Reference Helzlsouer, Erlinger and Platz2006). Furthermore, chronic use of aspirin and other anti-inflammatory drugs reduces the risk of cancers of the colon (Chan et al. Reference Chan, Giovannucci, Meyerhardt, Schernhammer, Curhan and Fuchs2005) and oesophagus (Vaughan et al. Reference Vaughan, Dong, Blount, Ayub, Odze, Sanchez, Rabinovitch and Reid2005). These various lines of evidence have focused attention on the molecular signals associated with inflammation, and on the phytochemicals that may modulate them.

NF-κB

NF-κB is a collective term for a family of dimeric proteins that act as transcription factors. In its inactive form NF-κB resides in the cytoplasm as a complex with the regulatory protein IκB. The activation pathway for NF-κB involves phosphorylation, of IκB by IκB kinase, leading to ubiquitination and proteolysis of IκB. This step frees NF-κB to translocate to the nucleus, where it binds to the κB sequence motif in DNA and acts as a transcription factor for at least 200 genes involved in the regulation of inflammation, cell proliferation, differentiation and apoptosis. NF-κB is constitutively activated in many tumours, and its key role as an up-regulator of inflammation suggests that it plays a key role in the earliest stages of promotion and progression (Karin et al. Reference Karin, Cao, Greten and Li2002).

A host of phytochemicals, including resveratrol, limonene, glycyrrhizin, gingerol, indole-3-carbinol, genistein, apigenin and many others, have been shown to inhibit NF-κB activity at various different stages in its regulatory pathway. For example, curcumin, a widely-studied anti-carcinogenic plant metabolite found in the spice cumin (Cuminum cyminum), suppresses TNF-induced activation of IκB kinase (Singh & Aggarwal, Reference Singh and Aggarwal1995), whereas caffeic acid phenethyl ester specifically prevents binding of NF-κB to its target DNA sequence (Natarajan et al. Reference Natarajan, Singh, Burke, Grunberger and Aggarwal1996). The downstream effects of NF-κB inhibitors include reduced expression of the key pro-inflammatory enzymes inducible NO synthase and cyclooxygenase (COX)-2.

Cyclooxygenase inhibitors

COX (PGH synthase) exists as two distinct isoforms; COX-1, which is constitutively expressed, produces PG essential to platelet aggregation and the maintenance of gastric mucosal integrity, whereas COX-2 is induced by tumour promoters and endogenous cytokines and produces PG involved in inflammatory processes. A third enzyme (COX-3) has been described that is a splice variant of COX-1, and its physiological role in man is not yet clear. Both COX-1 and COX-2 are inhibited by aspirin, an acetylated derivative of the secondary plant metabolite salicylate, originally isolated from willow (Salix alba). Both aspirin and salicylate irreversibly inhibit the COX enzymes by selectively acetylating the hydroxyl group of a single serine residue, and they both also suppress NF-κB by inhibiting IκB kinase kinase activity (Yin et al. Reference Yin, Yamamoto and Gaynor1998). There is abundant evidence that a number of flavonoids are COX-2 enzyme inhibitors (Baumann et al. Reference Baumann, von Bruchhausen and Wurm1980) and some (e.g. apigenin, chrysin and kaempferol) can suppress COX-2 transcription by mechanisms including activation of the PPARγ transcription factor (Liang et al. Reference Liang, Tsai, Tsai, Lin-Shiau and Lin2001) and inhibition of NF-κB expression (Liang et al. Reference Liang, Huang, Tsai, Lin-Shiau, Chen and Lin1999). Importantly, COX-2 transcription is inhibited in vitro not just by quercetin aglycone, but also by its human metabolites quercetin 3-glucuronide, quercetin 3′-sulfate and 3′-methylquercetin 3-glucuronide, and both quercetin and quercetin 3′-sulfate also inhibit COX-2 enzyme activity (O'Leary et al. Reference O'Leary, de Pascual-Tereasa, Needs, Bao, O'Brien and Williamson2004).

Direct inhibition of mitosis: the Wnt signalling pathway

The Wnt proteins are extracellular signalling molecules involved in the regulation of cell proliferation via the β-catenin signal pathway (Kundu et al. Reference Kundu, Choi and Surh2006). The nineteen known Wnt genes code for cysteine-rich glycoproteins; these proteins are released into the extracellular milieu where they modulate β-catenin signalling in target cells, via the membrane receptors Frizzled and LDL receptor-related protein. The intracellular protein β-catenin regulates many aspects of cellular organisation, ranging from cytoskeletal structure to the regulation of cell proliferation and death (Wikramanayake et al. Reference Wikramanayake, Hong, Lee, Pang, Byrum, Bince, Xu and Martindale2003). Levels of β-catenin in the cytoplasm are tightly regulated by a system of proteosomal degradation that begins when β-catenin forms a complex with the adenomatous polyposis coli protein and another scaffolding protein axin. This complex then associates with casein kinase I, which phosphorylates the N terminus of β-catenin, and glycogen synthase kinase 3β, which phosphorylates other β-catenin residues. The phosphorylated β-catenin molecule is then recognised by cytoplasmic β-transducin repeat-containing protein, which mediates its ubiquitination and degradation.

Wnt signalling plays an important role in gut formation during mammalian embyogenesis, and contributes to the maintenance of normal gut homeostasis in the adult. Disruption of Wnt signalling is a key abnormality during the development of cancers of the alimentary tract (Gregorieff & Clevers, Reference Gregorieff and Clevers2005). In normal cells there is a relatively large and stable pool of inactive β-catenin associated with the cytoskeletal protein cadherin, and a small labile pool in the cytoplasm. However, in cancer cells the degradation pathway is often suppressed and the balance is altered in favour of the cytoplasmic pool. Active β-catenin migrates to the nucleus, where it activates the lymphoid enhancer factor/T-cell factor family of transcription factors (T-cell factors 1, 3 and 4, lymphoid enhancer factor), freeing them from repression by groucho and histone deacetylase, and leading to the transcription of a variety of effector genes including C-myc, cyclin-D1, c-jun and COX-2. It is well established that synthetic COX-2 inhibitors, including indomethacin and aspirin, suppress β-catenin/T-cell factor-mediated gene transcription in colo-rectal carcinoma cells (Dihlmann et al. Reference Dihlmann, Siermann and von Knebel Doeberitz2001), and sulindac reduces nuclear β-catenin accumulation in the adenomatous polyps of patients with familial adenomatous polyposis (Boon et al. Reference Boon, Keller, Wormhoudt, Giardiello, Offerhaus, van der Neut and Pals2004). Moreover, a number of phytochemicals, including quercetin (Park et al. Reference Park, Chang, Hahm, Park, Kim and Yang2005), which suppresses colo-rectal crypt cell proliferation in the rat in vivo (Gee et al. Reference Gee, Hara and Johnson2002), also interact with the β-catenin pathway in vitro (Jaiswal et al. Reference Jaiswal, Marlow, Gupta and Narayan2002; Joe et al. Reference Joe, Liu, Suzui, Vural, Xiao and Weinstein2002). Dashwood et al. (Reference Dashwood, Orner and Dashwood2002) have shown that green tea, a minimally-processed ‘white’ tea and physiologically-relevant levels of epigallocatechin gallate all suppress nuclear β-catenin/T-cell factor 4 activity in HEK293 (kidney) cells in vitro. In the APC min mouse model of colo-rectal cancer, in which the adenomatous polyposis coli protein is disabled by an APC mutation, treatment with white tea, green tea or the non-steroidal anti-inflammatory drug sulindac all suppress tumourigenesis (Orner et al. Reference Orner, Dashwood, Blum, Diaz, Li and Dashwood2003). There was also evidence for suppression of β-catenin and its downstream products in the normal mucosa of mice treated with tea, and particularly in those treated with a combination of tea and sulindac.

Induction of apoptosis

Although the suppression of abnormal mitosis may slow the development of precancerous lesions and inhibit their competitive growth, the induction of programmed cell death can completely eliminate genetically-damaged cells from a tissue (Johnson, Reference Johnson2001). Several classes of phytochemicals, including organosulfur compounds (Xiao et al. Reference Xiao, Pinto, Gundersen and Weinstein2005) from garlic (Allium sativum) and ITC, have been shown to induce apoptosis in cell lines. Although glucosinolate breakdown products act as powerful inducers of phase II enzymes and modulate carcinogen metabolism in vitro and in vivo, it is unlikely to be their only mode of action; there is also much interest in their ability to block mitosis and initiate apoptosis in a variety of epithelial cell lines and tissues. Oral administration of the pure glucosinolate sinigrin (Smith et al. Reference Smith, Lund and Johnson1998), the precursor of allyl ITC, or raw Brussels sprouts (Brassica oleracea var. gemmifera) rich in sinigrin (Smith et al. Reference Smith, Mithen and Johnson2003) leads to an amplification of the apoptotic response occurring in colo-rectal crypts 48 h after exposure to the chemical carcinogen 1, 2 dimethylhydrazine. A high level of crypt-cell apoptosis is protective against colo-rectal neoplasia in both animal models (Chang et al. Reference Chang, Chapkin and Lupton1998) and human subjects (Martin et al. Reference Martin, Connelly, Keku, Mountcastle, Galanko, Woosley, Schliebe, Lund and Sandler2002). Importantly, the plasma and urinary metabolites to which the target tissues of human subjects are exposed in vivo may be just as effective as inducers of apoptosis as the parent ITC. Thus, the N-acetylcysteine conjugates of allyl ITC, benzyl ITC, phenethyl ITC and sulforaphane all readily inhibit proliferation and induce apoptosis in human bladder cancer cells (Tang et al. Reference Tang, Li, Song and Zhang2006). Furthermore, raw Brussels sprout juice exerts the same anti-proliferative effects as pure allyl ITC in vitro, yet contains no free allyl ITC (Smith et al. Reference Smith, Lund, Clarke, Bennett and Johnson2005). It is not entirely clear which of the other glucosinolate breakdown products and metabolites in raw Brussels sprout juice are responsible for this biological activity, but of those identified 1-cyano-2,3-epithiopropane, the gluconapin hydrolysis product, 3-butenyl isothiocyanate and the glucobrassicin metabolite ascorbigen are all candidates for this role. The mechanism of cell cycle arrest in vitro appears to involve a direct inhibition of tubulin polymerisation (Smith et al. Reference Smith, Lund, Parker, Clarke and Johnson2004, Reference Smith, Lund, Clarke, Bennett and Johnson2005), but the involvement of this mechanism in the induction of apoptosis in vivo remains to be established.

Molecular epidemiology

One effect of the discovery that certain biologically-active constituents of plants exert anti-carcinogenic effects in model systems has been to focus the attention of epidemiologists on the particular fruits, vegetables and beverages that contain them. Interest in the area has also encouraged a more hypothesis-driven approach to epidemiology and the use of Mendelian randomisation to explore the effects of genetic polymorphisms on the consequences of particular dietary exposures (Davey Smith & Ebrahim, Reference Davey Smith and Ebrahim2005). Studies on cruciferous vegetables provide some of the best examples of this trend, although the results are still rather ambiguous.

As mentioned previously, the GST superfamily contains a group of phase II detoxifying enzymes that metabolise environmental chemicals including carcinogens, drugs and phytochemicals. Approximately half the individuals in most human populations are homozygous for the null alleles of GSTT1 and GSTM1, and hence cannot express some important components of GST activity. These genotypes appear to carry little increased risk of lung cancer, but Lin et al. (Reference Lin, Probst-Hensch, Louie, Kau, Witte, Ingles, Frankl, Lee and Haile1998) have hypothesised that the GSTM1 null condition might lead to a slower rate of metabolism of glucosinolate breakdown products. In high consumers of brassica vegetables this reduced rate of metabolism might be expected to enhance the exposure of target tissues to ITC, and hence confer greater protection against cancer. To test this hypothesis Lin et al. (Reference Lin, Probst-Hensch, Louie, Kau, Witte, Ingles, Frankl, Lee and Haile1998) have conducted a case–control study of middle-aged patients undergoing screening sigmoidoscopy. A total of 459 cases having a first-time diagnosis of histologically-confirmed adenomas were compared with 507 controls with no polyp detected. Broccoli intake was assessed using a 126-item semi-quantitative FFQ. Subjects with the highest quartile of broccoli intake (3·7 servings per week) had an OR of 0·47 (95% CI 0·30, 0·73) for colo-rectal adenomas compared with subjects who ate no broccoli. When stratified by GSTM1 genotype this protective effect was observed only in patients null for GSTM1 (P<0·001 for trend; P<0·01 for interaction). However, Tijhuis et al. (Reference Tijhuis, Wark, Aarts, Visker, Nagengast, Kok and Kampman2005) have conducted a similar study in The Netherlands and have reported increased risk of adenomatous polyps amongst high consumers of cruciferous vegetables, an effect that was shown to be amplified in those with a single nucleotide polymorphism in GSTP1 (OR 1·94 (95% CI 1·02, 3·69)). No effects of the GSTT1 and GSTM1 deletion polymorphisms were observed. This unexpected finding might reflect differences in the population, the environment or the nature of the brassicas consumed, but it certainly deserves further investigation. Gasper et al. (Reference Gasper, Al-Janobi, Smith, Bacon, Fortun, Atherton, Taylor, Hawkey, Barrett and Mithen2005) have suggested that some of the contradictory reports concerning the protective effects of cruciferous vegetables against cancers of the lung and other sites might reflect varietal differences in the vegetables consumed by oriental and Western populations.

Unlike colo-rectal cancer, most lung cancer can be clearly linked to well-defined environmental carcinogens. GST enzymes are involved in the metabolism of both tobacco-smoke carcinogens and glucosinolate breakdown products, and a number of studies have been focused on the possibility of interactions between GST polymorphisms and the putative protective effects of cruciferous vegetables. Spitz et al. (Reference Spitz, Duphorne, Detry, Pillow, Amos, Lei, de Andrade, Gu, Hong and Wu2000) have undertaken a case–control study in which patients newly-diagnosed with lung cancer and their controls were genotyped for GSTM1 and GSTT1, and have reported on consumption of crucifers by means of a semi-quantitative FFQ. Overall, lower intake of cruciferous vegetables was reported by the cases compared with the controls (P=0·009). Amongst current cigarette smokers a low intake of crucifers was found to carry an OR of 2·22 (95% CI 1·2, 4·1) when combined with the GSTM1-null genotype and 3·19 (95% CI 1·54, 6·62) when combined with the GSTT1-null genotype. In individuals carrying both null genotypes and consuming low levels of crucifers the OR rises to 5·45 (95% CI 1·72, 17·22). In complete contrast to this finding, however, Zhao et al. (Reference Zhao, Seow, Lee, Poh, Teh, Eng, Wang, Tan, Yu and Lee2001) have conducted a similar study amongst female patients with lung cancer and controls in Singapore and have shown stronger protective effects of cruciferous vegetable intake in individuals with null genotypes for GSTM1 and GSTT1. For example, in those null for both alleles and consuming higher levels of cruciferous vegetables, the OR is 0·47 (95% CI 0·23, 0·95) compared with low consumers. Similar effects have been reported by London et al. (Reference London, Yuan, Chung, Gao, Coetzee, Ross and Yu2000), working with another Chinese population in which exposure to cruciferous vegetables was determined objectively using urinary excretion of ITC metabolites as a biomarker, and more recently by Brennan et al. (Reference Brennan, Hsu, Moullan, Szeszenia-Dabrowska, Lissowska and Zaridze2005), who have studied a central European population.

Generally speaking, phytochemicals are rather poorly absorbed by human subjects, and are themselves rapidly metabolised by the phase II enzymes. Much of this metabolism occurs in the gut mucosa (Fig. 2), and a large proportion of the resulting conjugates are actively secreted back into the gut lumen (Petri et al. Reference Petri, Tannergren, Holst, Mellon, Bao and Plumb2003). A recent study of the uptake and metabolism of the ITC sulforaphane from broccoli by human volunteers (Gasper et al. Reference Gasper, Al-Janobi, Smith, Bacon, Fortun, Atherton, Taylor, Hawkey, Barrett and Mithen2005) has demonstrated that in comparison with GSTM1-positive individuals those who are GSTM1 null excrete a greater proportion of the consumed dose of sulforaphane via the urine. They consider various possible explanations for this observation, and tentatively propose that expression of GSTM1 leads to retention of sulforaphane at some systemic site or sites, which facilitates its anti-carcinogenic activity. An alternative explanation may be that in the GSTM1-null individuals the absence of GSTM1 expression reduces the efficiency with which the ITC is transported back into the gut lumen following absorption (Petri et al. Reference Petri, Tannergren, Holst, Mellon, Bao and Plumb2003); however, further studies will be needed to resolve this issue.

Conclusion

Whatever the final assessment of the overall contribution of diets rich in fruits and vegetables to cancer prevention turns out to be, there is no doubt that the phytochemicals they contain do exert a range of fascinating and potentially-important biological effects on human cells. One obvious weakness of the current state of research, however, is that much of it has been conducted in vitro, with little regard for the bioavailability of the compounds studied. In most cases the small proportion of any compound that is absorbed undergoes extensive metabolism before reaching target organs, and the products are readily excreted. Although such phytochemicals cannot be regarded in any meaningful way as nutrients, their beneficial side effects may well be exploited in chemoprevention, much as those of drugs are, either by using pharmaceutical delivery systems, or through the development of ‘customised’ vegetables with high levels of selected phytochemicals (Mithen et al. Reference Mithen, Faulkner, Magrath, Rose, Williamson and Marquez2003). Such strategies will, however, require a full risk–benefit analysis, based on a thorough understanding of their overall biological effects.

Acknowledgements

The author acknowledges financial support from the Biotechnology and Biological Sciences Research Council and the EU. Thanks go to Tracy Smith and Paul Kroon for useful comments on the manuscript.

References

Askling, J, Grunewald, J, Eklund, A, Hillerdal, G & Ekbom, A (1999) Increased risk for cancer following sarcoidosis. American Journal of Respiratory and Critical Care Medicine 160, 16681672.CrossRefGoogle ScholarPubMed
Balkwill, F & Mantovani, A (2001) Inflammation and cancer: back to Virchow? Lancet 357, 539545.CrossRefGoogle ScholarPubMed
Baumann, J, von Bruchhausen, F & Wurm, G (1980) Flavonoids and related compounds as inhibition of arachidonic acid peroxidation. Prostaglandins 20, 627639.CrossRefGoogle ScholarPubMed
Block, G, Patterson, B & Subar, A (1992) Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutrition and Cancer 18, 129.CrossRefGoogle ScholarPubMed
Boon, EM, Keller, JJ, Wormhoudt, TA, Giardiello, FM, Offerhaus, GJ, van der Neut, R & Pals, ST (2004) Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colo-rectal cancer cell lines. British Journal of Cancer 90, 224229.CrossRefGoogle Scholar
Brennan, P, Hsu, CC, Moullan, N, Szeszenia-Dabrowska, N, Lissowska, J, Zaridze, D et al. (2005) Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a mendelian randomisation approach. Lancet 366, 15581560.CrossRefGoogle ScholarPubMed
Chan, AT, Giovannucci, EL, Meyerhardt, JA, Schernhammer, ES, Curhan, GC & Fuchs, CS (2005) Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colo-rectal cancer. Journal of the American Medical Association 294, 914923.CrossRefGoogle Scholar
Chang, WL, Chapkin, RS & Lupton, JR (1998) Fish oil blocks azoxymethane-induced rat colon tumorigenesis by increasing cell differentiation and apoptosis rather than decreasing cell proliferation. Journal of Nutrition 128, 491497.CrossRefGoogle ScholarPubMed
Chou, FP, Chu, YC, Hsu, JD, Chiang, HC & Wang, CJ (2000) Specific induction of glutathione S-transferase GSTM2 subunit expression by epigallocatechin gallate in rat liver. Biochemical Pharmacology 60, 643650.CrossRefGoogle ScholarPubMed
Dashwood, WM, Orner, GA & Dashwood, RH (2002) Inhibition of beta-catenin/Tcf activity by white tea, green tea, and epigallocatechin-3-gallate (EGCG): minor contribution of H(2)O(2) at physiologically relevant EGCG concentrations. Biochemical and Biophysical Research Communications 296, 584588.CrossRefGoogle ScholarPubMed
Davey Smith, G & Ebrahim, S (2005) What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? British Medical Journal 330, 10761079.CrossRefGoogle ScholarPubMed
Daviglus, ML, Liu, K, Pirzada, A, Yan, LL, Garside, DB, Wang, R et al. (2005) Relationship of fruit and vegetable consumption in middle-aged men to medicare expenditures in older age: the Chicago Western Electric Study. Journal of the American Dietetic Association 105, 17351744.CrossRefGoogle ScholarPubMed
Dihlmann, S, Siermann, A & von Knebel Doeberitz, M (2001) The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signalling. Oncogene 20, 645653.CrossRefGoogle Scholar
Ekbom, A, Helmick, C, Zack, M & Adami, HO (1990) Ulcerative colitis and colo-rectal cancer. A population-based study. New England Journal of Medicine 323, 12281233.CrossRefGoogle ScholarPubMed
Gasper, AV, Al-Janobi, A, Smith, JA, Bacon, JR, Fortun, P, Atherton, C, Taylor, MA, Hawkey, CJ, Barrett, DA & Mithen, RF (2005) Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. American Journal of Clinical Nutrition 82, 12831291.CrossRefGoogle ScholarPubMed
Gee, JM, Hara, H & Johnson, IT (2002) Suppression of intestinal crypt cell proliferation and aberrant crypt foci by dietary quercetin in rats. Nutrition and Cancer 43, 193201.CrossRefGoogle ScholarPubMed
Gregorieff, A & Clevers, H (2005) Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes and Development 19, 877890.CrossRefGoogle Scholar
He, FJ, Nowson, CA & MacGregor, GA (2006) Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 367, 320326.CrossRefGoogle ScholarPubMed
Hecht, SS, Carmella, SG, Kenney, PM, Low, SH, Arakawa, K & Yu, MC (2004) Effects of cruciferous vegetable consumption on urinary metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in Singapore Chinese. Cancer Epidemiology, Biomarkers and Prevention 13, 9971004.Google ScholarPubMed
Hecht, SS, Chung, FL, Richie, JP Jr, Akerkar, SA, Borukhova, A, Skowronski, L & Carmella, SG (1995) Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer Epidemiology, Biomarkers and Prevention 4, 877884.Google ScholarPubMed
Hecht, SS, Trushin, N, Rigotty, J, Carmella, SG, Borukhova, A, Akerkar, S & Rivenson, A (1996) Complete inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced rat lung tumorigenesis and favorable modification of biomarkers by phenethyl isothiocyanate. Cancer Epidemiology, Biomarkers and Prevention 5, 645652.Google ScholarPubMed
Helzlsouer, KJ, Erlinger, TP & Platz, EA (2006) C-reactive protein levels and subsequent cancer outcomes: results from a prospective cohort study. European Journal of Cancer 42, 704707.CrossRefGoogle ScholarPubMed
Houston, DK, Stevens, J, Cai, J & Haines, PS (2005) Dairy, fruit, and vegetable intakes and functional limitations and disability in a biracial cohort: the Atherosclerosis Risk in Communities Study. American Journal of Clinical Nutrition 81, 515522.CrossRefGoogle Scholar
International Agency for Research on Cancer (2003) Fruit and vegetables. Lyon, France: IARC Press.Google Scholar
Itoh, K, Chiba, T, Takahashi, S, Ishii, T, Igarashi, K, Katoh, Y et al. (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and Biophysical Research Communications 236, 313322.CrossRefGoogle ScholarPubMed
Jaiswal, AS, Marlow, BP, Gupta, N & Narayan, S (2002) Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21, 84148427.CrossRefGoogle ScholarPubMed
Joe, AK, Liu, H, Suzui, M, Vural, ME, Xiao, D & Weinstein, IB (2002) Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clinical Cancer Research 8, 893903.Google ScholarPubMed
Johnson, I, Williamson, G & Musk, S (1994) Anticarcinogenic factors in plant foods: a new class of nutrients? Nutrition Research Reviews 7, 175204.CrossRefGoogle ScholarPubMed
Johnson, IT (2001) Mechanisms and possible anticarcinogenic effects of diet related apoptosis in colo-rectal mucosa. Nutrition Research Reviews 14, 229256.CrossRefGoogle ScholarPubMed
Johnson, IT (2005) Cancers of the gut and Western ills. Science 307, 1839.CrossRefGoogle ScholarPubMed
Karin, M, Cao, Y, Greten, FR & Li, ZW (2002) NF-kappaB in cancer: from innocent bystander to major culprit. Nature Reviews Cancer 2, 301310.CrossRefGoogle ScholarPubMed
Key, TJ, Allen, N, Appleby, P, Overvad, K, Tjonneland, A, Miller, A et al. (2004) Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). International Journal of Cancer 109, 119124.CrossRefGoogle Scholar
Kundu, JK, Choi, K-Y & Surh, Y-J (2006) Beta-catenin-mediated sinalling: A novel molecular target for chemoprevention with anti-inflammatory substances. Biochimica et Biophysica Acta 1765, 1424.Google ScholarPubMed
Lambrix, V, Reichelt, M, Mitchell-Olds, T, Kliebenstein, DJ & Gershenzon, J (2001) The Arabidopsis epithiospecifier protein promotes the hydrolysis of glucosinolates to nitriles and influences Trichoplusia ni herbivory. Plant Cell 13, 27932807.CrossRefGoogle ScholarPubMed
Liang, YC, Huang, YT, Tsai, SH, Lin-Shiau, SY, Chen, CF & Lin, JK (1999) Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis 20, 19451952.CrossRefGoogle ScholarPubMed
Liang, YC, Tsai, SH, Tsai, DC, Lin-Shiau, SY & Lin, JK (2001) Suppression of inducible cyclooxygenase and nitric oxide synthase through activation of peroxisome proliferator-activated receptor-gamma by flavonoids in mouse macrophages. FEBS Letters 496, 1218.CrossRefGoogle ScholarPubMed
Lin, HJ, Probst-Hensch, NM, Louie, AD, Kau, IH, Witte, JS, Ingles, SA, Frankl, HD, Lee, ER & Haile, RW (1998) Glutathione transferase null genotype, broccoli, and lower prevalence of colo-rectal adenomas. Cancer Epidemiology, Biomarkers and Prevention 7, 647652.Google Scholar
London, SJ, Yuan, JM, Chung, FL, Gao, YT, Coetzee, GA, Ross, RK & Yu, MC (2000) Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China. Lancet 356, 724729.CrossRefGoogle ScholarPubMed
McDanell, R, McLean, AE, Hanley, AB, Heaney, RK & Fenwick, GR (1988) Chemical and biological properties of indole glucosinolates (glucobrassicins): a review. Food and Chemical Toxicology 26, 5970.CrossRefGoogle ScholarPubMed
McWalter, GK, Higgins, LG, McLellan, LI, Henderson, CJ, Song, L, Thornalley, PJ, Itoh, K, Yamamoto, M & Hayes, JD (2004) Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. Journal of Nutrition 134, 3499S3506S.CrossRefGoogle ScholarPubMed
Macarthur, M, Hold, GL & El-Omar, EM (2004) Inflammation and cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. American Journal of Physiology 286, G515G520.Google ScholarPubMed
Martin, C, Connelly, A, Keku, TO, Mountcastle, SB, Galanko, J, Woosley, JT, Schliebe, B, Lund, PK & Sandler, RS (2002) Nonsteroidal anti-inflammatory drugs, apoptosis, and colo-rectal adenomas. Gastroenterology 123, 17701777.CrossRefGoogle Scholar
Miao, W, Hu, L, Scrivens, PJ & Batist, G (2005) Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. Journal of Biological Chemistry 280, 2034020348.CrossRefGoogle ScholarPubMed
Michels, KB, Edward, G, Joshipura, KJ, Rosner, BA, Stampfer, MJ, Fuchs, CS, Colditz, GA, Speizer, FE & Willett, WC (2000) Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. Journal of the National Cancer Institute 92, 17401752.CrossRefGoogle ScholarPubMed
Mithen, R, Faulkner, K, Magrath, R, Rose, P, Williamson, G & Marquez, J (2003) Development of isothiocyanate-enriched broccoli, and its enhanced ability to induce phase 2 detoxification enzymes in mammalian cells. Theoretical and Applied Genetics 106, 727734.CrossRefGoogle ScholarPubMed
Mithen, RF, Dekker, M, Verkerk, R, Rabot, S & Johnson, IT (2000) The nutritional significance, biosynthesis and bioavailability of glucosinolates in human foods. Journal of the Science of Food and Agriculture 80, 967984.3.0.CO;2-V>CrossRefGoogle Scholar
Morse, MA, LaGreca, SD, Amin, SG & Chung, FL (1990) Effects of indole-3-carbinol on lung tumorigenesis and DNA methylation induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and on the metabolism and disposition of NNK in A/J mice. Cancer Research 50, 26132617.Google Scholar
Natarajan, K, Singh, S, Burke, TR Jr, Grunberger, D & Aggarwal, BB (1996) Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proceedings of the National Academy of Sciences USA 93, 90909095.CrossRefGoogle ScholarPubMed
Nelson, DR, Kamataki, T, Waxman, DJ, Guengerich, FP, Estabrook, RW, Feyereisen, R et al. (1993) The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA and Cell Biology 12, 151.CrossRefGoogle ScholarPubMed
O'Leary, KA, de Pascual-Tereasa, S, Needs, PW, Bao, YP, O'Brien, NM & Williamson, G (2004) Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutation Research 551, 245254.CrossRefGoogle ScholarPubMed
Orner, GA, Dashwood, WM, Blum, CA, Diaz, GD, Li, Q & Dashwood, RH (2003) Suppression of tumorigenesis in the Apc(min) mouse: down-regulation of beta-catenin signaling by a combination of tea plus sulindac. Carcinogenesis 24, 263267.CrossRefGoogle ScholarPubMed
Park, CH, Chang, JY, Hahm, ER, Park, S, Kim, HK & Yang, CH (2005) Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochemical and Biophysical Research Communications 328, 227234.CrossRefGoogle ScholarPubMed
Petri, N, Tannergren, C, Holst, B, Mellon, FA, Bao, Y, Plumb, GW et al. (2003) Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo. Drug Metabolism and Disposition 31, 805813.CrossRefGoogle Scholar
Prochaska, HJ & Talalay, P (1988) Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Research 48, 47764782.Google ScholarPubMed
Rouzaud, G, Rabot, S, Ratcliffe, B & Duncan, AJ (2003) Influence of plant and bacterial myrosinase activity on the metabolic fate of glucosinolates in gnotobiotic rats. British Journal of Nutrition 90, 395404.CrossRefGoogle ScholarPubMed
Rouzaud, G, Young, SA & Duncan, AJ (2004) Hydrolysis of glucosinolates to isothiocyanates after ingestion of raw or microwaved cabbage by human volunteers. Cancer Epidemiology, Biomarkers and Prevention 13, 125131.CrossRefGoogle ScholarPubMed
Singh, S & Aggarwal, BB (1995) Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane). Journal of Biological Chemistry 270, 2499525000.CrossRefGoogle Scholar
Smith, TK, Lund, EK, Clarke, RG, Bennett, RN & Johnson, IT (2005) Effects of Brussels sprout juice on the cell cycle and adhesion of human colo-rectal carcinoma cells (HT29) in vitro. Journal of Agricultural and Food Chemistry 53, 38953901.CrossRefGoogle Scholar
Smith, TK, Lund, EK & Johnson, IT (1998) Inhibition of dimethylhydrazine-induced aberrant crypt foci and induction of apoptosis in rat colon following oral administration of the glucosinolate sinigrin. Carcinogenesis 19, 267273.CrossRefGoogle ScholarPubMed
Smith, TK, Lund, EK, Parker, ML, Clarke, RG & Johnson, IT (2004) Allyl-isothiocyanate causes mitotic block, loss of cell adhesion and disrupted cytoskeletal structure in HT29 cells. Carcinogenesis 25, 14091415.CrossRefGoogle ScholarPubMed
Smith, TK, Mithen, R & Johnson, IT (2003) Effects of Brassica vegetable juice on the induction of apoptosis and aberrant crypt foci in rat colonic mucosal crypts in vivo. Carcinogenesis 24, 491495.CrossRefGoogle ScholarPubMed
Smith-Warner, SA, Spiegelman, D, Yaun, SS, Adami, HO, Beeson, WL, van den Brandt, PA et al. (2001) Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. Journal of the American Medical Association 285, 769776.CrossRefGoogle ScholarPubMed
Smith-Warner, SA, Spiegelman, D, Yaun, SS, Albanes, D, Beeson, WL, van den Brandt, PA et al. (2003) Fruits, vegetables and lung cancer: a pooled analysis of cohort studies. International Journal of Cancer 107, 10011011.CrossRefGoogle ScholarPubMed
Spitz, MR, Duphorne, CM, Detry, MA, Pillow, PC, Amos, CI, Lei, L, de Andrade, M, Gu, X, Hong, WK & Wu, X (2000) Dietary intake of isothiocyanates: evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk. Cancer Epidemiology, Biomarkers and Prevention 9, 10171020.Google ScholarPubMed
Steinmetz, KA & Potter, JD (1996) Vegetables, fruit, and cancer prevention: a review. Journal of the American Dietetic Association 96, 10271039.CrossRefGoogle ScholarPubMed
Talalay, P & Fahey, JW (2001) Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. Journal of Nutrition 131, 3027S3033S.Google ScholarPubMed
Tang, L, Li, G, Song, L & Zhang, Y (2006) The principal urinary metabolites of dietary isothiocyanates, N-acetylcysteine conjugates, elicit the same anti-proliferative response as their parent compounds in human bladder cancer cells. Anticancer Drugs 17, 297305.CrossRefGoogle ScholarPubMed
Terry, P, Terry, JB & Wolk, A (2001) Fruit and vegetable consumption in the prevention of cancer: an update. Journal of Internal Medicine 250, 280290.CrossRefGoogle ScholarPubMed
Tijhuis, MJ, Wark, PA, Aarts, JM, Visker, MH, Nagengast, FM, Kok, FJ & Kampman, E (2005) GSTP1 and GSTA1 polymorphisms interact with cruciferous vegetable intake in colo-rectal adenoma risk. Cancer Epidemiology, Biomarkers and Prevention 14, 29432951.CrossRefGoogle Scholar
van Gils, CH, Peeters, PH, Bueno-de-Mesquita, HB, Boshuizen, HC, Lahmann, PH, Clavel-Chapelon, F et al. (2005) Consumption of vegetables and fruits and risk of breast cancer. Journal of the American Medical Association 293, 183193.CrossRefGoogle ScholarPubMed
Vaughan, TL, Dong, LM, Blount, PL, Ayub, K, Odze, RD, Sanchez, CA, Rabinovitch, PS & Reid, BJ (2005) Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study. Lancet Oncology 6, 945952.CrossRefGoogle ScholarPubMed
Wattenberg, LW (1975 a) Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Research 35, 33263331.Google Scholar
Wattenberg, LW (1975 b) Inhibition of dimethylhydrazine-induced neoplasia of the large intestine by disulfiram. Journal of the National Cancer Institute 54, 10051006.CrossRefGoogle ScholarPubMed
Wattenberg, LW (1985) Chemoprevention of cancer. Cancer Research 45, 18.Google ScholarPubMed
Wikramanayake, AH, Hong, M, Lee, PN, Pang, K, Byrum, CA, Bince, JM, Xu, R & Martindale, MQ (2003) An ancient role for nuclear beta-catenin in the evolution of axial polarity and germ layer segregation. Nature 426, 446450.CrossRefGoogle ScholarPubMed
World Cancer Research Fund (1997) Food, Nutrition and the Prevention of Cancer: A Global Perspective, pp. 216251. Washington, DC: American Institute for Cancer Research.Google Scholar
Xiao, D, Pinto, JT, Gundersen, GG & Weinstein, IB (2005) Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells. Molecular Cancer Therapeutics 4, 13881398.CrossRefGoogle ScholarPubMed
Yin, MJ, Yamamoto, Y & Gaynor, RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396, 7780.CrossRefGoogle ScholarPubMed
Zhao, B, Seow, A, Lee, EJ, Poh, WT, Teh, M, Eng, P, Wang, YT, Tan, WC, Yu, MC & Lee, HP (2001) Dietary isothiocyanates, glutathione S-transferase-M1, -T1 polymorphisms and lung cancer risk among Chinese women in Singapore. Cancer Epidemiology, Biomarkers and Prevention 10, 10631067.Google ScholarPubMed

Altmetric attention score

Full text views

Full text views reflects PDF downloads, PDFs sent to Google Drive, Dropbox and Kindle and HTML full text views.

Total number of HTML views: 611
Total number of PDF views: 1298 *
View data table for this chart

* Views captured on Cambridge Core between September 2016 - 6th March 2021. This data will be updated every 24 hours.

Access

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Phytochemicals and cancer
Available formats
×

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Phytochemicals and cancer
Available formats
×

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Phytochemicals and cancer
Available formats
×
×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *