Efficacy of Herbal Products in Colorectal Cancer Prevention

Genoveva Murillo, PhD, RD, Rajesh Naithani, PhD, and Rajendra G. Mehta, PhD

Corresponding author Rajendra G. Mehta, PhD Carcinogenesis and Chemoprevention Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616, USA. E-mail: RMehta@iitri.org Current Colorectal Cancer Reports 2008, 4:3442 Current Medicine Group LLC ISSN 1556-3790 Copyright 2008 by Current Medicine Group LLC

as an anti-inflammatory, antibacterial, and antiseptic herbal powder. Furthermore, many of our synthetic drugs (eg, paclitaxel and camptothecin) originate from plants that contain selective anticancer agents.

What Is an Herb?
Generally, herbs can be divided into two categories: culinary and medicinal. Culinary herbs traditionally make use of the green, leafy part of the plant; any other part of the plant, often dried, is commonly referred to as a spice. Spices can be buds (cloves), roots (ginger), seeds (cumin), or barks (cinnamon). Onions and garlic are often classified as herbs primarily because they are used fresh and applied in a similar way to cooking. Medicinal herbs, by definition, include leaves, roots, flowers, seed, inner bark, berries, and oils. Moreover, any edible plant (eg, fruits) may be considered an herb in medicinal use [2]. The National Institutes of Healths Office of Dietary Supplements defines an herbal product as a botanical that is used to maintain or improve health [3]. Other accepted nomenclature for herbal products includes medicinal herbs, botanical products, natural herbs, and phytomedicines. This review includes traditional herbals plus any component of an edible plant that has been used as a medicinal herb. Given the multitude of herbal medicines, it is not possible to discuss all of them. The review provides a synopsis of the most commonly used herbs in the United States that have been investigated specifically for prevention of colorectal cancer (CRC).

Colorectal cancer (CRC) continues to be a leading cause of mortality and morbidity in the United States. Cancer chemopreventionthe use of specic pharmacologic agents or nutrients to prevent, reverse, or inhibit the process of carcinogenesisis an attractive approach. The cancer chemopreventive potential of herbs has been of great interest, in part because it has been reported that about one third of the US population regularly consumes one or more herbal supplements. This review describes the CRC chemopreventive effects of herbal products identied by the National Health Interview Survey to be the most widely consumed in the United States. This report summarizes published studies of chemopreventive and cytotoxic effects of herbs in human colon cancer cells, proposed molecular mechanisms, efcacy studies using in vivo CRC models, and epidemiologic studies.

Introduction
Herbs are believed to be humanitys first medicines, having been used by ancient cultures in Asia, Africa, Europe, and the Americas. The Ebers papyrus (1500 BC), one of the most important ancient Egyptian medical papyri, describes the medicinal uses of several herbs, including coriander, cumin, and garlic [1]. Likewise, historical documents from ancient Greece and Rome describe the use of mint (digestive tract), licorices (anti-inflammatory, asthma), and rosemary (memory). Hippocrates was reported to have used garlic to treat uterine cancer [2]. In Asia, the wide use of herbs for medicinal purposes continues. Ayurveda, the ancient science of health and medicine native to the Indian subcontinent, focuses on disease prevention and health promotion and emphasizes the use of herbs and spices [1]. For example, turmeric is commonly used

The Use of Herbs for CRC Prevention

Despite the increased attention paid to screening programs for CRC, this disease continues to be one of the leading cancers in the United States, with an estimated 153,760 new cases expected in 2007 [4]. The effort to prevent CRC has targeted chemoprevention and early detection through screening. Cancer chemoprevention is defined as pharmacologic intervention with synthetic or naturally occurring compounds that may prevent, inhibit, or reverse carcinogenesis or prevent the development of invasive cancer. Dietary consumption of foods

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Murillo et al. 35

Table 1. Herbs reported to exhibit chemopreventive efcacy against colorectal cancer*

Herb Cascara sagrada (Rhamnus purshiana) Chasteberry/vitex (Vitex angus; castus fruit) Echinacea Active components Unknown Extract Polysaccharides, avonoids, glycoproteins Extract Parthenolide Organic sulfurs Gingerol Gingkolides Ginsenosides Proanthrocyanides, avonoids Unknown Molecular mechanisms of action Cell cycle arrest, apoptosis, cell adhesion Apoptosis Apoptosis US consumers, n [3] 663,000 179,000 14,665,000 Articles on Medline, n [3] 2 1 1

Evening primrose Feverfew Garlic Ginger Ginkgo biloba Ginseng Hawthorn fruit Licorice (Glycyrrhiza glabra) Milk thistle (Silbum marianum, Gaertneri) Saw palmetto (Serenoa repens) Senna Soy St. Johns wort Yohimbine

Apoptosis Growth inhibitor Cell cycle, P450 inhibitor, COX-2 inhibitor, antioxidant COX-2 inhibitor Antioxidant, anti-inammatory, fewer precancerous lesions P450 inhibitor, COX-2 inhibitor Antioxidant COX-2 inhibitor, antioxidant, apoptosis, topoisomerase II inhibitor COX-2 inhibitor, fewer tumors Apoptosis, growth inhibitor Fewer precancerous lesions Antioxidant, topoisomerase II inhibitor, cell cycle arrest Antioxidant, apoptosis, antiproliferative Growth inhibitor

1,686,000 865,000 7,096,000 3,768,000 7,679,000 8,777,000 733,000 1,469,000

1 1 46 6 2 11 1 4

Unknown Unknown Anthraquinone Flavonoids, genistein Hypericin, rubin, quercetin Indole alkaloids

1,255,000 2,054,000 361,000 3,480,000 4,390,000 633,000

1 1 3 58 5 4

*Of the herbs identied by the National Health Interview Survey (NHIS) as most widely consumed in the United States [3]. COX-2cyclooxygenase-2.

and herbal products has been considered an appropriate way of administering beneficial phytochemicals. Because herbal products are derived from edible plants, they are not are not subject to the same government regulation as other pharmaceuticals. These factors have contributed to the growing interest in herbs by the public and the scientific community. Recent findings estimate that approximately 45% of disease-free Americans use alternative modalities, including herbal medicine, for disease prevention and therapy [5]. Several national surveys have shown that the number of Americans using herbs to treat diseases and improve illness is growing [3,5,6]. In 1990, it was estimated that 2.5% of the US population used one or more herbs for medicinal purposes. In 2002, the percentage of Americans using herbal products increased to 18.6%approximately 38 million people [6]. Given the large number of herbs avail-

able, the herbs reviewed in this article were selected from those identified by the National Health Interview Survey (NHIS) as most commonly used by adults in the United States [3]. Of the 29 herbs identified by the NHIS, a systematic review of Medline identified 17 herbs that have been investigated in relation to CRC. Of the 17 herbs listed on Table 1, five (garlic, ginger, ginseng, soy, and St. Johns wort), along with their main constituents, were found to be the most widely studied for their CRC chemopreventive properties. These herbs are discussed in this review.

Garlic
Garlic is an almost universally consumed food and medicinal herb. It is derived from the bulbs that form on the stem of the plant. Garlic is a rich source of vitamin A and B-complex vitamins, and it can contain high

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Prevention and Early Detection

Herb

Agents/ compounds

Structures of some constituent molecules

S S S Diallyl sulde NH2 S Allicin O O OH CH3 MeO OH OH 6-Paradol S S-allylcysteine O CH3 OH O

Diallyl disulde

Garlic

Organosulfur compounds

Ginger

Gingerols

MeO OH 6-Gingerol

Ginseng

Saponins Polysaccharides Flavonoids Volatile oils

HO

O OH OH O

HO

O OH OH OH O Quercetin

OH

Kaempferol

HO

HO

OH

OH

OH HO CH3 OH H H H3C CH 3 H

O Daidzein CH3 CH3

Soy

Isoavones Saponins Sphingolipids Trypsin inhibitors

Genistein

OH HO OH Soyasapogenol B

HO H3C

CH3 Folienetriol OH O OH

H CH3

St. Johns wort

Volatile oils Anthraquinones Carotenoids Coumarin Flavonoids

HO

OH MeO OH O

HO HO

CH3 CH3

Phloroglucinol

OH

Pinostrobin

OH

OH

Hypericin

Figure 1. Herbs, their active components, and structures of some constituent molecules.

levels of trace minerals such as selenium. The major component of garlic is organosulfur (Fig. 1), the compound responsible for its unique odor. Folklore medicine has found a wide array of uses for garlic, ranging from relief of insect bites to control of blood pressure. The recommended dosage is about 4 g of fresh garlic daily,

which is equivalent to 8 mg of garlic oil or 600 to 800 mg of garlic powder preparation standardized to 1.3% allicin content [7]. Discovery of the numbers of allylic sulfur compounds in garlic [8] and their mechanisms has provided scientific validation for its chemopreventive effects.

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Murillo et al. 37

Epidemiology and clinical evidence

Epidemiologic data support the protective role of garlic against the development of CRC [9,10]. Fleischauer and Arab [10] recently summarized these data. Three case-control and three cohort studies suggest that garlic (raw, cooked, or both) may provide a protective effect against CRC. On the other hand, studies investigating the role of garlic supplements have not always yielded supportive outcomes. For example, Dorant et al. [9] did not find any significant inverse association between consumption of onions, leeks, or garlic supplements and the incidence of CRC. These data suggest that raw or cooked fresh garlic consumed over an extended period, rather than intake of garlic supplements, may provide the greatest chemopreventive effects.

Epidemiology and clinical evidence

No human studies have been conducted to evaluate gingers CRC chemopreventive properties, but in vitro studies and studies in animals support its use for the prevention of colorectal cancer.

Experimental evidence
Gingers active components have been reported to exhibit cancer-preventive activity in several experimental carcinogenesis models. For example, zerumbone, a sesquiterpene in rhizomes, has been shown to inhibit the growth of colon cancer cell lines (LS174T, LS180, Colo 205, and Colo 320DM) in a dose-dependent fashion with maximum inhibition found at a dose of 50 M [17]. Zerumbone (50 M) was found to induce apoptosis in Colo 205 cells in a time-dependent manner. Chromatin condensation was noted in cells treated with zerumbone. One study in rats investigated the effects of oral ginger (50 mg/kg/d) on colon carcinogenesis induced by 15 weekly injections of DMH (20 mg/kg) [18]. Lipid peroxidation properties were measured on the basis of thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes; antioxidant status was measured using superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, reduced glutathione, and vitamins C, E, and A. In rats given DMH, plasma lipid peroxidation and cancer incidence were significantly increased, whereas antioxidant concentrations were decreased as compared with control rats. The number of tumors and the incidence of cancer were significantly decreased in animals given ginger in the diet. Circulating lipid peroxidation was significantly reduced in all ginger-treatment groups, and enzymatic and nonenzymatic antioxidants were enhanced in the ginger-supplemented animals. Manju and Nalini [19] investigated the efficacy of ginger on the activity of colonic bacterial microflora (mucinase and -glucuronidase) in rats with colon cancer induced by DMH. The microflora were selected, in part, because -glucuronidase is responsible for degrading the glucuronide conjugates, with the production of toxins and carcinogens, whereas mucinase breaks down mucins. Male Wistar rats were injected with subcutaneous DMH (20 mg/kg) once a week for 15 weeks. Ginger (50 mg/kg/d) was given orally at the initiation and postinitiation stages of carcinogenesis. The rats were killed 30 weeks after the initiation of DMH, and the activity of mucinase and -glucuronidase was measured in the tissues and fecal contents. Animals receiving ginger during both the initiation and postinitiation periods had significantly fewer tumors than the controls. Furthermore, enzyme activity of mucinase and -glucuronidase was significantly reduced in the tissues and fecal matter of rats receiving ginger as compared with control animals. These data suggest that ginger may protect against colon cancer by regulating the levels of intestinal microflora.

Experimental evidence
The active components of garlic have been shown to mediate chemopreventive effects in both experimental models of colon carcinogenesis and cell culture systems. The incidence of aberrant crypt foci (ACF) in azoxymethane (AOM)-induced colon carcinogenesis in rats was reduced 32.11% by 2% (weight/volume) dietary administration of garlic, 76.14% by tomato, and 55.96% by a combination of both [11]. Assays for in situ cell proliferation and apoptosis revealed a significant reduction in the bromodeoxyuridine (BrdU) labeling index and an increase in the apoptotic index in the colons of animals receiving tomato or garlic in their diets, suggesting that dietary consumption of tomato and garlic has a protective effect against colon carcinogenesis. Similarly, dietary administration of aged garlic extract (AGE), an odorless garlic product, has been reported to significantly suppress the formation of ACF and tumors in 1,2-dimethylhydrazine (DMH)induced colon carcinogenesis [12]. Likewise, individual components of garlic have demonstrated chemopreventive efficacy in animal models. For example, diallyl sulfide (DAS), a principal component of garlic, has been shown to reduce the formation of ACF significantly (43.65%) in AOM-induced colon carcinogenesis, in part by reducing the expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase [13]. Likewise, in vitro studies have helped to elucidate the mechanisms of action associated with garlics chemopreventive effects. In colon cancer cells, garlic and its constituents have been shown to induce apoptosis [14,15], regulate the cell cycle [14], induce histone acetylation [16], and upregulate tumor suppressors such as p21Waf1/Cip1 [14].

Ginger
Ginger is derived from the underground stem and root of a tropical plant (Zingiber officinale) native to eastern Asia. It has been used traditionally by many cultures for flavoring and as medicine. It is still commonly used for illnesses of the digestive system such as nausea from morning sickness or motion sickness.

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Prevention and Early Detection

In contrast, Dias et al. [20] failed to find a chemopreventive effect for ginger using the DMH-induced ACF model in male Wistar rats. The animals were injected with DMH (40 mg/kg twice a week for 2 weeks) before being fed either a basal diet or a meal containing 0.5% or 1.0% ginger extract for 10 weeks. Following the ginger treatment, the animals were killed and ACF formation was evaluated. Ginger meal at 0.5% and 1.0% failed to reduce the number and size of ACF. In this study, the carcinogen was administered at a much higher dose and frequency than in the other studies [18,19], which may explain why no effect was noted in the ginger-fed rats. Another possibility is that a null effect was noted because ginger was provided after the carcinogen exposure. Ginger may be acting primarily as an anti-initiator, possibly by altering the microflora, as reported by others [18,19].

cancer cases (58 people) was 0.3 (95% CI, 0.20.7) among consumers of fresh ginseng extract and 0.3 (95% CI, 0.10.7) for those consuming mixed types of ginseng. It was observed that ginseng extract and powder were more effective than fresh sliced ginseng, ginseng juice, or ginseng tea for reducing the risk of cancer [23].

Experimental evidence
Experimental models have been instrumental in establishing the efficacy of ginseng against colon carcinogenesis. For example, using Korean red ginseng powder (0.5 and 2.0 mg/kg for 5 weeks), it was shown that the progression of established ACF can be significantly inhibited [24]. Similarly, histologic analysis of colon mucosa of mice receiving red ginseng powder versus control diet revealed that ginseng may be suppressing the appearance of ACF by inducing apoptosis [25]. Cell culture studies provide further support for the apoptosis-inducing abilities of ginseng [26]. Other mechanisms proposed for ginseng include antioxidant activity, P450 inhibition, and COX-2 inhibition [27].

Ginseng
Ginseng is a root that is one of the most popular herbs of the East and West. It includes species from Asia (Panax ginseng, often called Chinese or Korean ginseng) and North America (P. quinquefolius, called American ginseng). Historically, ginseng has been used to regulate blood pressure, enhance memory, and stimulate immunity [17]. Although no recommended dosage is available for cancer prevention, it has been suggested that 200 mg/d of standardized extract (4% ginsenosides) may be beneficial for patients suffering from hypertension, cardiovascular disease, or diabetes. The principal components of ginseng include saponins, polysaccharides, flavonoids, and volatile oils (Fig. 1) [21]. Cancer chemoprevention studies have largely examined the efficacy of ginseng ginsenosides.

Soy
Soy is a subtropical plant native to southeastern Asia. This member of the pea family (Fabaceae) has been a dietary staple in Asia for many centuries. Soy was introduced to Europe in the 1700s and to the United States in the 1800s. Epidemiologic data support the use of soybeans for general well-being [28]. Several biologically active components in soy may contribute individually and in combination to its proposed chemopreventive properties. Among the components of soy that have been investigated in relation to CRC are isoflavones (genistein and daidzein), saponins, sphingolipids, and trypsin inhibitors (Fig. 1). In recent years, its popularity has increased as much as fourfold in the United States, and isoflavone supplements have been widely consumed [28]. No dietary recommendations have been made for soy, but it has been suggested that up to 75 mg/d of isoflavones (equivalent to a minimum of 25 g of soy protein) may be necessary for cancer prevention [28].

Epidemiology and clinical evidence

Several studies in Korea have investigated the efficacy of ginseng on the risk for several types of cancers [22,23]. In a large-scale case-control study in Seoul, Korea, interviews were conducted in 905 pairs of cancer patients and controls matched for age, sex, and date of admission to the hospital [22]. Of the 905 cancer patients, 62% had consumed ginseng, versus 75% of controls, indicating a significant statistical difference (P < 0.01) between consumers and nonconsumers. The odds ratio of all cancer types in relation to ginseng consumption was 0.6 (95% CI, 0.50.7). Moreover, for CRC a decrease in risk was associated with a higher frequency and longer duration of ginseng intake, suggesting a dose-response relationship. Patients who had taken ginseng for 1 year had a 36% lower incidence of CRC during that year than nonusers, whereas those who had used ginseng for 5 years or more had a 69% lower incidence. Similarly, a prospective study was conducted to evaluate the preventive effects of ginseng [23]. A total 4675 subjects were interviewed in Kanghwa-eup, an area of Korea where ginseng is commonly produced. In a 5-year follow-up period, the relative risk for newly diagnosed

Epidemiology and clinical evidence

Historically low rates of breast and prostate cancer in Asia have been attributed in part to the high consumption of soy [28]. Moreover, limited evidence also suggests that soy may be protective against the development of CRC [2931]. A recent review summarized the association between soy consumption and CRC risk [31]. A total of 13 epidemiologic studies meeting the inclusion criteria were evaluated; they cumulatively suggest an inverse association between CRC and soy intake. Even though a trend was noted, however, the confidence interval crossed 1.0 for most of the studies. Weaknesses in the study designs included problems with dietary questionnaires, inappropriate periods for cancer prevention, and inadequate adjustment for confounders. It was concluded that observational studies generally tend

Efficacy of Herbal Products in Colorectal Cancer Prevention

Murillo et al. 39

to underestimate the association. In light of this unclear association between soy and CRC risk in humans, investigations in animals and tissue culture have sought to better elucidate the role of soy and its active components in CRC.

St. Johns Wort

St. Johns wort (SJW) preparations are derived from the leaves and flowers of a common North American and European perennial (Hypericum perforatum), which has been used in folklore medicine as a topical wound healer. Oral intake of SJW traditionally has been used to alleviate symptoms of depression, insomnia, and anxiety. Several biologically active compounds in SJW have been reported. The major constituents commonly found in SJW preparations include volatile oils (0.05%0.3%, including -pinene and cineole), anthraquinones, carotenoids, coumarin, flavonoids (0.5%1.0%, including hyperoside, quercetin, and rutin), naphthodianthrones (0.1%0.3%, of which 80%90% are hypericin and pseudohypericin), canthones, and proanthocyanidins (Fig. 1) [38]. Several of these active compounds have been reported to possess anticancer activities.

Experimental evidence
For the most part, the ability of soy to inhibit colon cancer in animals remains unclear. In carcinogen-treated rodents, soy and its biologically active components have yielded positive, null, and negative results. In our laboratory, we examined the effects of soybean flour (10% of diet) and compared its efficacy to that of garbanzo flour (10% of diet) or a combination of both (5% soy and 5% garbanzo flour) in AOM-induced ACF in CF1 mice [32]. Dietary treatments in AOM-treated mice showed a 64% (P < 0.001) suppression of ACF in animals fed garbanzo flour versus 58% inhibition with soy flour and 55% with the mixed flours (P < 0.001). Although we examined the role of whole foods (soy and garbanzo flour), many others have investigated the role of individual compounds of soy. For example, Symolon et al. [33] examined the efficacy of soy sphingolipids against DMH-induced colon tumorigenesis in CF1 and APC Min/+ mice. Sphingolipids were added to the diet of mice treated with DMH (as 0%, 0.025%, or 0.1% of the diet by weight). Administration of soy sphingolipids was shown to significantly reduce the number of ACF in CF1 mice and adenomas in APC Min/+ mice. Furthermore, the effects of dietary sphingolipids on gene expression in the intestinal mucosal cells of APC Min mice revealed downregulation of two transcription factors associated with cancer, hypoxiainduced factor 1 and transcription factor 4. Although the two studies just discussed [32,33] support the chemopreventive actions of soy, others have reported no effect. For example, Sorensen et al. [34] reported a lack of inhibitory effect by isoflavones in APC Min mice fed a Western-style (high-fat/low-fiber/low-calcium) diet containing 16 to 475 mg/kg soy isoflavones. Others have reported enhanced induction of ACF, colon tumors, or both by various components of soy, including soy isoflavones [35] and purified genistein or genistein-rich soya protein [36]. Cumulatively, these studies demonstrate that although consuming soybean products may provide chemoprotection, use of soy isoflavone supplements may have adverse effects against colon cancer, at least in susceptible populations such as breast cancer survivors and postmenopausal women. Data from in vitro experiments have been more concordant on the chemopreventive potential of isoflavone-rich soybean products. Several potential mechanisms have been proposed for the anticancer effect of soy (particularly genistein), including inhibition of DNA topoisomerase and tyrosine kinase activity, as well as antioxidant properties [37]. Furthermore, treatment of colon cancer cells with soy components has been shown to inhibit the activity of cdc2 kinase, induce apoptosis, and result in G2/M-phase cell-cycle arrest [37]. The relative importance of each of these mechanisms remains to be determined in vivo.

Epidemiology and clinical evidence

There are no articles concerning the anticancer efficacy of SJW in humans.

Experimental evidence
Extracts of the plant H. perforatum have been used for centuries in traditional medicine, notably to treat depression. A main component, hypericin, has been identified as the molecule responsible for the antidepressant effects of this plant. Within the last few years, the role of hypericininduced photocytotoxicity has been investigated in colon cancer cells [39]. Sackov et al. [40] examined the efficacy of hypericin photocytotoxicity on the HT-29 human colon cancer cell line and the U937 human myeloid leukemia cell line. For these experiments, cells were treated with hypericin at increasing concentrations, and experiments were conducted on cell viability, cell number, cell cycle regulation, and apoptosis. Cells were incubated in the dark for 16 hours with 1 10 -9 M to 1 10 -6 M concentrations of hypericin before being irradiated with a single light dose (4.4 J/cm2). The two cell lines showed different growth inhibitory patterns: the HT-29 colon cancer line was less sensitive to hypericin (IC50 = 1 10 -7 M) than the U937 leukemia line (IC50 = 1 10 -8 M). Changes in the cell cycle distribution were also different among the two cell lines tested. HT-29 cells incubated at 1 10 -7 M hypericin were found to arrest in the G2/M phase of the cell cycle, whereas the U937 cells exhibited an S-phase arrest. In the HT-29 cells, cell cycle arrest was accompanied by apoptosis. Thus these studies support the efficacy of hypericin against colon cancer and leukemia. Hypericin may mediate its protective effects by inducing cell cycle arrest and apoptosis. In addition to having antiproliferative and apoptotic effects, it has been proposed that SJW acts as an antioxidant and electrophile scavenger, inhibits the formation of DNA adducts with carcinogens, inhibits hormonal actions and metabolic pathways associated with the development of cancer, and mediates anti-inflammatory actions in various organs [4044].

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Table 2. Evidence supporting the efcacy of herbs against colorectal cancer

Epidemiologic/clinical studies Animal studies Garlic and garlic + tomato: decreased ACF in AOM-induced colon cancer in rats [11] Aged garlic extract: decreased DMH-induced colon tumors in rats [12] Diallyl sulde: decreased formation of ACF in AOM-induced colon cancer in rats; decreased expression of COX-2 and iNOS [13] Prospective [10] 1 Decreased DMH-induced colon tumors in rats [18]: decreased lipid peroxidation, increased antioxidant activity No studies available on CRC prevention Decreased DMH-induced colon tumors in rats [19]: decreased mucinase and -glucuronidase levels Ginger meal diet: no decrease in DMH-induced ACF in rats Korean red ginseng powder: decreased progression of ACF [24] Red ginseng: decreased ACF and induced apoptosis in colonic crypts [25] Soy our: decreased incidence of ACF in AOM-induced colon cancer [32] Soy sphingolipids: inhibited ACF in DMH-induced colon cancer in CF1 mice; inhibited tumors in APCMin/+ mice [33] Isoavones: decrease, enhance, or have no effect on incidence of ACF and tumors [3436] No studies available on CRC prevention Case-control [22] Prospective [23] Ecological Case-control 1 1 3 9 Supportive Supportive Both fermented and non-fermented soy products: protective trend, but condence intervals overlap 1.0 in most studies [31] Cohort 1 Case-control [9] 3 Cohort [9] 3 Type No. of studies Result All supportive All supportive Garlic supplements: no association

Herb

In vitro studies (cell lines)

Garlic

Apoptosis (Caco-2, HT-29, Colo 205); increased caspase 3 activity and BAX expression (Colo 205); G1 arrest (HT-29, Caco-2); upregulation of p21Waf1/Cip1; induction of histone acetylation (HT-29) [1416]

Prevention and Early Detection

Ginger

Apoptosis (Colo 205); growth inhibition (LS174T, LS180, Colo 205, Colo 320DM) [17]

Ginseng

Apoptosis, antioxidant (HCT-116) [26,27]

Soy

G2/M arrest (HT-29); inhibition of cdc2 kinase, apoptosis, inhibition of DNA topoisomerase, inhibition of tyrosine kinase (HT-29, Caco-2) [37]

St. Johns wort

Decreased cell viability (HT-29); G2/M arrest (Caco-2); apoptosis (HT-29, Colo 205) [3944]

No studies available on CRC prevention

ACFaberrant crypt foci; AOMazoxymethane; COX-2cyclooxygenase-2; CRCcolorectal cancer; DMH1,2-dimethylhydrazine; iNOSinducible nitric oxide synthase.

Efficacy of Herbal Products in Colorectal Cancer Prevention

Murillo et al. 41

Conclusions
A wide array of herbs, commonly consumed around the world, contain bioactive molecules of interest for colon cancer prevention. The evidence for each of the five herbs discussed in this review is summarized in Table 2. A few other herbal products with promise for CRC prevention include curcumin, components in green and black tea, herbal oils (d-limonene, Perillyl alcohol), and resveratrol, a potent antioxidant extracted from grapes [45]. Several in-depth reviews have recently been published demonstrating the chemopreventive uses of these herbs [24,46,47]. Cumulatively, research shows that herbs are a complex natural mixture simultaneously influencing different stages of carcinogenesis (tumor initiation, promotion, and progression) via different mechanisms of action. Furthermore, given that it takes more than 10 years for cancer to develop, it is difficult to determine the chemopreventive contribution of each individual herb or to know whether the chemoprotection comes from consuming a combination of herbs during a specific stage of carcinogenesis. In general, it appears that fresh herbs may be superior to many of the supplements sold in health food stores. This difference may be related to the lack of regulation of what goes into the supplements. Additionally, it is important to note that some herbal products may produce adverse effects in certain populations (eg, postmenopausal women, smokers). Therefore, although history has shown that natural herbal products promote well-being and prevent disease, they must first undergo scientific validation similar to that of synthetic drugs if they are going to be used therapeutically or by highrisk individuals. Studies elucidating their mechanisms of action will help to determine which specific conditions and populations will benefit most from their consumption.

4. 5.

6. 7. 8. 9. 10. 11. 12. 13.

14.

15. 16.

17.

Disclosures
No potential conflict of interest relevant to this article was reported.

18.

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