Efficacy of Herbal Products in Colorectal Cancer Prevention Murillo et al. 35 Table 1. Herbs reported to exhibit chemopreventive efﬁcacy against colorectal cancer* Molecular mechanisms Articles on Herb Active components of action US consumers, n  Medline, n  Cascara sagrada Unknown Cell cycle arrest, apoptosis, 663,000 2 (Rhamnus purshiana) cell adhesion Chasteberry/vitex Extract Apoptosis 179,000 1 (Vitex angus; castus fruit) Echinacea Polysaccharides, Apoptosis 14,665,000 1 ﬂavonoids, glycoproteins Evening primrose Extract Apoptosis 1,686,000 1 Feverfew Parthenolide Growth inhibitor 865,000 1 Garlic Organic sulfurs Cell cycle, P450 inhibitor, 7,096,000 46 COX-2 inhibitor, antioxidant Ginger Gingerol COX-2 inhibitor 3,768,000 6 Ginkgo biloba Gingkolides Antioxidant, anti-inﬂammatory, 7,679,000 2 fewer precancerous lesions Ginseng Ginsenosides P450 inhibitor, COX-2 inhibitor 8,777,000 11 Hawthorn fruit Proanthrocyanides, Antioxidant 733,000 1 ﬂavonoids Licorice Unknown COX-2 inhibitor, antioxidant, 1,469,000 4 (Glycyrrhiza glabra) apoptosis, topoisomerase II inhibitor Milk thistle (Silbum Unknown COX-2 inhibitor, fewer tumors 1,255,000 1 marianum, Gaertneri) Saw palmetto Unknown Apoptosis, growth inhibitor 2,054,000 1 (Serenoa repens) Senna Anthraquinone Fewer precancerous lesions 361,000 3 Soy Flavonoids, genistein Antioxidant, topoisomerase II 3,480,000 58 inhibitor, cell cycle arrest St. John’s wort Hypericin, rubin, Antioxidant, apoptosis, 4,390,000 5 quercetin antiproliferative Yohimbine Indole alkaloids Growth inhibitor 633,000 4 *Of the herbs identiﬁed by the National Health Interview Survey (NHIS) as most widely consumed in the United States . COX-2—cyclooxygenase-2.and herbal products has been considered an appropriate able, the herbs reviewed in this article were selected fromway of administering beneficial phytochemicals. Because those identified by the National Health Interview Surveyherbal products are derived from edible plants, they are (NHIS) as most commonly used by adults in the Unitednot are not subject to the same government regulation as States . Of the 29 herbs identified by the NHIS, a system-other pharmaceuticals. These factors have contributed atic review of Medline identified 17 herbs that have beento the growing interest in herbs by the public and the investigated in relation to CRC. Of the 17 herbs listed onscientific community. Table 1, five (garlic, ginger, ginseng, soy, and St. John’s Recent findings estimate that approximately 45% of wort), along with their main constituents, were found todisease-free Americans use alternative modalities, includ- be the most widely studied for their CRC chemopreventiveing herbal medicine, for disease prevention and therapy . properties. These herbs are discussed in this review.Several national surveys have shown that the number ofAmericans using herbs to treat diseases and improve illnessis growing [3,5,6]. In 1990, it was estimated that 2.5% of Garlicthe US population used one or more herbs for medicinal Garlic is an almost universally consumed food andpurposes. In 2002, the percentage of Americans using medicinal herb. It is derived from the bulbs that formherbal products increased to 18.6%—approximately 38 on the stem of the plant. Garlic is a rich source of vita-million people . Given the large number of herbs avail- min A and B-complex vitamins, and it can contain high
36 Prevention and Early Detection Agents/ Herb compounds Structures of some constituent molecules S S S Diallyl disulﬁde Diallyl sulﬁde Garlic Organosulfur NH2 compounds S O S S Allicin O S-allylcysteine OH O OH O MeO MeO Ginger Gingerols CH3 CH3 6-Gingerol 6-Paradol OH OH OH Saponins HO O HO O OH Ginseng Polysaccharides Flavonoids OH OH OH Volatile oils OH O OH O Kaempferol Quercetin HO O HO O OH OH O OH O OH HO Isoﬂavones Genistein Daidzein Soyasapogenol B Saponins OH Soy HO CH3 Sphingolipids OH CH3 Trypsin inhibitors H H CH3 H3C CH 3 H CH3 HO H3C H CH3 Folienetriol OH O OH Volatile oils Anthraquinones HO OH St. John’s Carotenoids O HO CH3 MeO wort Coumarin HO CH3 Flavonoids OH OH O Phloroglucinol OH O OH Pinostrobin HypericinFigure 1. Herbs, their active components, and structures of some constituent molecules.levels of trace minerals such as selenium. The major which is equivalent to 8 mg of garlic oil or 600 to 800component of garlic is organosulfur (Fig. 1), the com- mg of garlic powder preparation standardized to 1.3%pound responsible for its unique odor. Folklore medicine allicin content . Discovery of the numbers of allylichas found a wide array of uses for garlic, ranging from sulfur compounds in garlic  and their mechanismsrelief of insect bites to control of blood pressure. The has provided scientific validation for its chemopreven-recommended dosage is about 4 g of fresh garlic daily, tive effects.
Efficacy of Herbal Products in Colorectal Cancer Prevention Murillo et al. 37Epidemiology and clinical evidence Epidemiology and clinical evidenceEpidemiologic data support the protective role of gar- No human studies have been conducted to evaluatelic against the development of CRC [9,10]. Fleischauer ginger’s CRC chemopreventive properties, but in vitroand Arab  recently summarized these data. Three studies and studies in animals support its use for the pre-case-control and three cohort studies suggest that garlic vention of colorectal cancer.(raw, cooked, or both) may provide a protective effectagainst CRC. On the other hand, studies investigating Experimental evidencethe role of garlic supplements have not always yielded Ginger’s active components have been reported to exhibitsupportive outcomes. For example, Dorant et al.  cancer-preventive activity in several experimental carcino-did not find any significant inverse association between genesis models. For example, zerumbone, a sesquiterpeneconsumption of onions, leeks, or garlic supplements and in rhizomes, has been shown to inhibit the growth of colonthe incidence of CRC. These data suggest that raw or cancer cell lines (LS174T, LS180, Colo 205, and Colocooked fresh garlic consumed over an extended period, 320DM) in a dose-dependent fashion with maximumrather than intake of garlic supplements, may provide inhibition found at a dose of 50 μM . Zerumbone (50the greatest chemopreventive effects. μM) was found to induce apoptosis in Colo 205 cells in a time-dependent manner. Chromatin condensation wasExperimental evidence noted in cells treated with zerumbone.The active components of garlic have been shown to medi- One study in rats investigated the effects of oralate chemopreventive effects in both experimental models ginger (50 mg/kg/d) on colon carcinogenesis inducedof colon carcinogenesis and cell culture systems. The by 15 weekly injections of DMH (20 mg/kg) . Lipidincidence of aberrant crypt foci (ACF) in azoxymethane peroxidation properties were measured on the basis(AOM)-induced colon carcinogenesis in rats was reduced of thiobarbituric acid reactive substances, lipid hydro-32.11% by 2% (weight/volume) dietary administration of peroxides, and conjugated dienes; antioxidant status wasgarlic, 76.14% by tomato, and 55.96% by a combination of measured using superoxide dismutase, catalase, glutathi-both . Assays for in situ cell proliferation and apoptosis one peroxidase, glutathione-S-transferase, glutathionerevealed a significant reduction in the bromodeoxyuridine reductase, reduced glutathione, and vitamins C, E, and A.(BrdU) labeling index and an increase in the apoptotic In rats given DMH, plasma lipid peroxidation and cancerindex in the colons of animals receiving tomato or garlic in incidence were significantly increased, whereas antioxi-their diets, suggesting that dietary consumption of tomato dant concentrations were decreased as compared withand garlic has a protective effect against colon carcinogene- control rats. The number of tumors and the incidencesis. Similarly, dietary administration of aged garlic extract of cancer were significantly decreased in animals given(AGE), an odorless garlic product, has been reported to ginger in the diet. Circulating lipid peroxidation wassignificantly suppress the formation of ACF and tumors in significantly reduced in all ginger-treatment groups, and1,2-dimethylhydrazine (DMH)–induced colon carcinogene- enzymatic and nonenzymatic antioxidants were enhancedsis . Likewise, individual components of garlic have in the ginger-supplemented animals.demonstrated chemopreventive efficacy in animal models. Manju and Nalini  investigated the efficacy of gin-For example, diallyl sulfide (DAS), a principal component ger on the activity of colonic bacterial microflora (mucinaseof garlic, has been shown to reduce the formation of ACF and -glucuronidase) in rats with colon cancer inducedsignificantly (43.65%) in AOM-induced colon carcinogene- by DMH. The microflora were selected, in part, becausesis, in part by reducing the expression of cyclooxygenase -glucuronidase is responsible for degrading the glucu-(COX)-2 and inducible nitric oxide synthase . Likewise, ronide conjugates, with the production of toxins andin vitro studies have helped to elucidate the mechanisms carcinogens, whereas mucinase breaks down mucins.of action associated with garlic’s chemopreventive effects. Male Wistar rats were injected with subcutaneous DMHIn colon cancer cells, garlic and its constituents have been (20 mg/kg) once a week for 15 weeks. Ginger (50 mg/kg/d)shown to induce apoptosis [14,15], regulate the cell cycle was given orally at the initiation and postinitiation stages, induce histone acetylation , and upregulate tumor of carcinogenesis. The rats were killed 30 weeks aftersuppressors such as p21Waf1/Cip1 . the initiation of DMH, and the activity of mucinase and -glucuronidase was measured in the tissues and fecal con- tents. Animals receiving ginger during both the initiationGinger and postinitiation periods had significantly fewer tumorsGinger is derived from the underground stem and root of a than the controls. Furthermore, enzyme activity of muci-tropical plant (Zingiber officinale) native to eastern Asia. nase and -glucuronidase was significantly reduced in theIt has been used traditionally by many cultures for flavor- tissues and fecal matter of rats receiving ginger as com-ing and as medicine. It is still commonly used for illnesses pared with control animals. These data suggest that gingerof the digestive system such as nausea from morning may protect against colon cancer by regulating the levelssickness or motion sickness. of intestinal microflora.
38 Prevention and Early Detection In contrast, Dias et al.  failed to find a chemo- cancer cases (58 people) was 0.3 (95% CI, 0.2–0.7) amongpreventive effect for ginger using the DMH-induced ACF consumers of fresh ginseng extract and 0.3 (95% CI,model in male Wistar rats. The animals were injected with 0.1–0.7) for those consuming mixed types of ginseng. ItDMH (40 mg/kg twice a week for 2 weeks) before being was observed that ginseng extract and powder were morefed either a basal diet or a meal containing 0.5% or 1.0% effective than fresh sliced ginseng, ginseng juice, or gin-ginger extract for 10 weeks. Following the ginger treat- seng tea for reducing the risk of cancer .ment, the animals were killed and ACF formation wasevaluated. Ginger meal at 0.5% and 1.0% failed to reduce Experimental evidencethe number and size of ACF. In this study, the carcinogen Experimental models have been instrumental in establish-was administered at a much higher dose and frequency ing the efficacy of ginseng against colon carcinogenesis. Forthan in the other studies [18,19], which may explain why example, using Korean red ginseng powder (0.5 and 2.0no effect was noted in the ginger-fed rats. Another possi- mg/kg for 5 weeks), it was shown that the progression ofbility is that a null effect was noted because ginger was established ACF can be significantly inhibited . Simi-provided after the carcinogen exposure. Ginger may be larly, histologic analysis of colon mucosa of mice receivingacting primarily as an anti-initiator, possibly by altering red ginseng powder versus control diet revealed that ginsengthe microflora, as reported by others [18,19]. may be suppressing the appearance of ACF by inducing apoptosis . Cell culture studies provide further support for the apoptosis-inducing abilities of ginseng . OtherGinseng mechanisms proposed for ginseng include antioxidantGinseng is a root that is one of the most popular herbs of activity, P450 inhibition, and COX-2 inhibition .the East and West. It includes species from Asia (Panaxginseng, often called Chinese or Korean ginseng) and NorthAmerica (P. quinquefolius, called American ginseng). His- Soytorically, ginseng has been used to regulate blood pressure, Soy is a subtropical plant native to southeastern Asia. Thisenhance memory, and stimulate immunity . Although member of the pea family (Fabaceae) has been a dietaryno recommended dosage is available for cancer prevention, staple in Asia for many centuries. Soy was introduced toit has been suggested that 200 mg/d of standardized extract Europe in the 1700s and to the United States in the 1800s.(4% ginsenosides) may be beneficial for patients suffering Epidemiologic data support the use of soybeans for generalfrom hypertension, cardiovascular disease, or diabetes. The well-being . Several biologically active components inprincipal components of ginseng include saponins, polysac- soy may contribute individually and in combination to itscharides, flavonoids, and volatile oils (Fig. 1) . Cancer proposed chemopreventive properties. Among the compo-chemoprevention studies have largely examined the efficacy nents of soy that have been investigated in relation to CRCof ginseng ginsenosides. are isoflavones (genistein and daidzein), saponins, sphingo- lipids, and trypsin inhibitors (Fig. 1). In recent years, itsEpidemiology and clinical evidence popularity has increased as much as fourfold in the UnitedSeveral studies in Korea have investigated the efficacy of States, and isoflavone supplements have been widely con-ginseng on the risk for several types of cancers [22,23]. In sumed . No dietary recommendations have been madea large-scale case-control study in Seoul, Korea, interviews for soy, but it has been suggested that up to 75 mg/d of iso-were conducted in 905 pairs of cancer patients and controls flavones (equivalent to a minimum of 25 g of soy protein)matched for age, sex, and date of admission to the hospi- may be necessary for cancer prevention .tal . Of the 905 cancer patients, 62% had consumedginseng, versus 75% of controls, indicating a significant Epidemiology and clinical evidencestatistical difference (P < 0.01) between consumers and non- Historically low rates of breast and prostate cancer in Asiaconsumers. The odds ratio of all cancer types in relation to have been attributed in part to the high consumption of soyginseng consumption was 0.6 (95% CI, 0.5–0.7). Moreover, . Moreover, limited evidence also suggests that soy mayfor CRC a decrease in risk was associated with a higher fre- be protective against the development of CRC [29–31]. Aquency and longer duration of ginseng intake, suggesting a recent review summarized the association between soy con-dose-response relationship. Patients who had taken ginseng sumption and CRC risk . A total of 13 epidemiologicfor 1 year had a 36% lower incidence of CRC during that studies meeting the inclusion criteria were evaluated; theyyear than nonusers, whereas those who had used ginseng cumulatively suggest an inverse association between CRCfor 5 years or more had a 69% lower incidence. and soy intake. Even though a trend was noted, however, Similarly, a prospective study was conducted to evalu- the confidence interval crossed 1.0 for most of the studies.ate the preventive effects of ginseng . A total 4675 Weaknesses in the study designs included problems withsubjects were interviewed in Kanghwa-eup, an area of dietary questionnaires, inappropriate periods for cancerKorea where ginseng is commonly produced. In a 5-year prevention, and inadequate adjustment for confounders.follow-up period, the relative risk for newly diagnosed It was concluded that observational studies generally tend
Efficacy of Herbal Products in Colorectal Cancer Prevention Murillo et al. 39to underestimate the association. In light of this unclear St. John’s Wortassociation between soy and CRC risk in humans, investi- St. John’s wort (SJW) preparations are derived from thegations in animals and tissue culture have sought to better leaves and flowers of a common North American andelucidate the role of soy and its active components in CRC. European perennial (Hypericum perforatum), which has been used in folklore medicine as a topical wound healer.Experimental evidence Oral intake of SJW traditionally has been used to alleviateFor the most part, the ability of soy to inhibit colon cancer symptoms of depression, insomnia, and anxiety. Several bio-in animals remains unclear. In carcinogen-treated rodents, logically active compounds in SJW have been reported. Thesoy and its biologically active components have yielded major constituents commonly found in SJW preparationspositive, null, and negative results. In our laboratory, we include volatile oils (0.05%–0.3%, including -pinene andexamined the effects of soybean flour (10% of diet) and cineole), anthraquinones, carotenoids, coumarin, flavonoidscompared its efficacy to that of garbanzo flour (10% of diet) (0.5%–1.0%, including hyperoside, quercetin, and rutin),or a combination of both (5% soy and 5% garbanzo flour) naphthodianthrones (0.1%–0.3%, of which 80%–90% arein AOM-induced ACF in CF1 mice . Dietary treatments hypericin and pseudohypericin), canthones, and proantho-in AOM-treated mice showed a 64% (P < 0.001) suppres- cyanidins (Fig. 1) [38••]. Several of these active compoundssion of ACF in animals fed garbanzo flour versus 58% have been reported to possess anticancer activities.inhibition with soy flour and 55% with the mixed flours(P < 0.001). Although we examined the role of whole foods Epidemiology and clinical evidence(soy and garbanzo flour), many others have investigated the There are no articles concerning the anticancer efficacy ofrole of individual compounds of soy. For example, Symo- SJW in humans.lon et al.  examined the efficacy of soy sphingolipidsagainst DMH-induced colon tumorigenesis in CF1 and Experimental evidenceAPC Min/+ mice. Sphingolipids were added to the diet of mice Extracts of the plant H. perforatum have been used fortreated with DMH (as 0%, 0.025%, or 0.1% of the diet by centuries in traditional medicine, notably to treat depres-weight). Administration of soy sphingolipids was shown to sion. A main component, hypericin, has been identified assignificantly reduce the number of ACF in CF1 mice and the molecule responsible for the antidepressant effects ofadenomas in APC Min/+ mice. Furthermore, the effects of this plant. Within the last few years, the role of hypericin-dietary sphingolipids on gene expression in the intestinal induced photocytotoxicity has been investigated in colonmucosal cells of APC Min mice revealed downregulation of cancer cells . Sacková et al.  examined the efficacytwo transcription factors associated with cancer, hypoxia- of hypericin photocytotoxicity on the HT-29 human coloninduced factor 1 and transcription factor 4. cancer cell line and the U937 human myeloid leukemia cell Although the two studies just discussed [32,33] support line. For these experiments, cells were treated with hyperi-the chemopreventive actions of soy, others have reported cin at increasing concentrations, and experiments wereno effect. For example, Sorensen et al.  reported a lack conducted on cell viability, cell number, cell cycle regula-of inhibitory effect by isoflavones in APC Min mice fed a tion, and apoptosis. Cells were incubated in the dark forWestern-style (high-fat/low-fiber/low-calcium) diet contain- 16 hours with 1 × 10 -9 M to 1 × 10 -6 M concentrations ofing 16 to 475 mg/kg soy isoflavones. Others have reported hypericin before being irradiated with a single light doseenhanced induction of ACF, colon tumors, or both by vari- (4.4 J/cm2). The two cell lines showed different growthous components of soy, including soy isoflavones  and inhibitory patterns: the HT-29 colon cancer line was lesspurified genistein or genistein-rich soya protein . Cumu- sensitive to hypericin (IC50 = 1 × 10 -7 M) than the U937latively, these studies demonstrate that although consuming leukemia line (IC50 = 1 × 10 -8 M). Changes in the cell cyclesoybean products may provide chemoprotection, use of soy distribution were also different among the two cell linesisoflavone supplements may have adverse effects against tested. HT-29 cells incubated at 1 × 10 -7 M hypericin werecolon cancer, at least in susceptible populations such as found to arrest in the G2/M phase of the cell cycle, whereasbreast cancer survivors and postmenopausal women. the U937 cells exhibited an S-phase arrest. In the HT-29 Data from in vitro experiments have been more concor- cells, cell cycle arrest was accompanied by apoptosis. Thusdant on the chemopreventive potential of isoflavone-rich these studies support the efficacy of hypericin against colonsoybean products. Several potential mechanisms have cancer and leukemia. Hypericin may mediate its protectivebeen proposed for the anticancer effect of soy (particularly effects by inducing cell cycle arrest and apoptosis.genistein), including inhibition of DNA topoisomerase and In addition to having antiproliferative and apoptotictyrosine kinase activity, as well as antioxidant properties effects, it has been proposed that SJW acts as an antioxi-. Furthermore, treatment of colon cancer cells with dant and electrophile scavenger, inhibits the formationsoy components has been shown to inhibit the activity of of DNA adducts with carcinogens, inhibits hormonalcdc2 kinase, induce apoptosis, and result in G2/M-phase actions and metabolic pathways associated with thecell-cycle arrest . The relative importance of each of development of cancer, and mediates anti-inflammatorythese mechanisms remains to be determined in vivo. actions in various organs [40–44].
40Table 2. Evidence supporting the efﬁcacy of herbs against colorectal cancer Epidemiologic/clinical studiesHerb In vitro studies (cell lines) Animal studies Type No. of studies ResultGarlic Apoptosis (Caco-2, HT-29, Colo 205); Garlic and garlic + tomato: decreased ACF in Cohort  3 All supportive increased caspase 3 activity and AOM-induced colon cancer in rats  BAX expression (Colo 205); Aged garlic extract: decreased DMH-induced Case-control  3 All supportive G1 arrest (HT-29, Caco-2); colon tumors in rats  upregulation of p21Waf1/Cip1; induction of histone acetylation Diallyl sulﬁde: decreased formation of ACF in Prospective  1 Garlic supplements: (HT-29) [14–16] AOM-induced colon cancer in rats; decreased no association expression of COX-2 and iNOS Ginger Apoptosis (Colo 205); Decreased DMH-induced colon tumors in rats No studies — — growth inhibition (LS174T, LS180, : decreased lipid peroxidation, increased available on Prevention and Early Detection Colo 205, Colo 320DM)  antioxidant activity CRC prevention Decreased DMH-induced colon tumors in rats : decreased mucinase and -glucuronidase levels Ginger meal diet: no decrease in DMH-induced ACF in ratsGinseng Apoptosis, antioxidant (HCT-116) Korean red ginseng powder: Case-control  1 Supportive [26,27] decreased progression of ACF  Red ginseng: decreased ACF and induced Prospective  1 Supportive apoptosis in colonic crypts Soy G2/M arrest (HT-29); inhibition of cdc2 Soy ﬂour: decreased incidence of ACF in Ecological 3 Both fermented and kinase, apoptosis, inhibition of DNA AOM-induced colon cancer  non-fermented soy topoisomerase, inhibition of tyrosine Soy sphingolipids: inhibited ACF in Case-control 9 products: protective kinase (HT-29, Caco-2)  DMH-induced colon cancer in CF1 mice; trend, but conﬁdence inhibited tumors in APCMin/+ mice  intervals overlap 1.0 in most studies  Isoﬂavones: decrease, enhance, or have Cohort 1 no effect on incidence of ACF and tumors [34–36]St. John’s wort Decreased cell viability (HT-29); No studies available on CRC prevention No studies — — G2/M arrest (Caco-2); apoptosis available on (HT-29, Colo 205) [39–44] CRC preventionACF—aberrant crypt foci; AOM—azoxymethane; COX-2—cyclooxygenase-2; CRC—colorectal cancer; DMH—1,2-dimethylhydrazine; iNOS—inducible nitric oxide synthase.
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