Download - 35 colorectal
Corresponding authorRajendra G. Mehta, PhDCarcinogenesis and Chemoprevention Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616, USA.E-mail: [email protected]
Current Colorectal Cancer Reports 2008, 4:34–42Current Medicine Group LLC ISSN 1556-3790Copyright © 2008 by Current Medicine Group LLC
Colorectal cancer (CRC) continues to be a leading cause of mortality and morbidity in the United States. Cancer chemoprevention—the use of specific pharma-cologic agents or nutrients to prevent, reverse, or inhibit the process of carcinogenesis—is 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 identified 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, efficacy studies using in vivo CRC models, and epidemiologic studies.
IntroductionHerbs are believed to be humanity’s 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 Likewise, historical documents from ancient Greece and Rome describe the use of mint (digestive tract), licorices (anti-inflammatory, asthma), and rosemary (memory).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
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: culi-nary 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 Health’s 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 phyto-medicines. 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 pro-vides a synopsis of the most commonly used herbs in the United States that have been investigated specifically for prevention of colorectal cancer (CRC).
The Use of Herbs for CRC PreventionDespite the increased attention paid to screening pro-grams 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 develop-ment of invasive cancer. Dietary consumption of foods
Efficacy of Herbal Products in Colorectal Cancer PreventionGenoveva Murillo, PhD, RD, Rajesh Naithani, PhD,
and Rajendra G. Mehta, PhD
Efficacy of Herbal Products in Colorectal Cancer Prevention Murillo et al. 35
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, includ-ing 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 system-atic 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. John’s 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.
GarlicGarlic 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 vita-min A and B-complex vitamins, and it can contain high
Table 1. Herbs reported to exhibit chemopreventive efficacy against colorectal cancer*
Herb Active componentsMolecular mechanisms
of action US consumers, n [3]Articles on
Medline, n [3]
Cascara sagrada (Rhamnus purshiana)
Unknown Cell cycle arrest, apoptosis, cell adhesion
663,000 2
Chasteberry/vitex (Vitex angus; castus fruit)
Extract Apoptosis 179,000 1
Echinacea Polysaccharides, flavonoids,
glycoproteins
Apoptosis 14,665,000 1
Evening primrose Extract Apoptosis 1,686,000 1
Feverfew Parthenolide Growth inhibitor 865,000 1
Garlic Organic sulfurs Cell cycle, P450 inhibitor, COX-2 inhibitor, antioxidant
7,096,000 46
Ginger Gingerol COX-2 inhibitor 3,768,000 6
Ginkgo biloba Gingkolides Antioxidant, anti-inflammatory, fewer precancerous lesions
7,679,000 2
Ginseng Ginsenosides P450 inhibitor, COX-2 inhibitor 8,777,000 11
Hawthorn fruit Proanthrocyanides, flavonoids
Antioxidant 733,000 1
Licorice (Glycyrrhiza glabra)
Unknown COX-2 inhibitor, antioxidant, apoptosis, topoisomerase II
inhibitor
1,469,000 4
Milk thistle (Silbum marianum, Gaertneri)
Unknown COX-2 inhibitor, fewer tumors 1,255,000 1
Saw palmetto (Serenoa repens)
Unknown Apoptosis, growth inhibitor 2,054,000 1
Senna Anthraquinone Fewer precancerous lesions 361,000 3
Soy Flavonoids, genistein Antioxidant, topoisomerase II inhibitor, cell cycle arrest
3,480,000 58
St. John’s wort Hypericin, rubin, quercetin
Antioxidant, apoptosis, antiproliferative
4,390,000 5
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 [3].COX-2—cyclooxygenase-2.
36 Prevention and Early Detection
levels of trace minerals such as selenium. The major component of garlic is organosulfur (Fig. 1), the com-pound 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 chemopreven-tive effects.
Volatile oilsAnthraquinonesCarotenoidsCoumarinFlavonoids
Gingerols
Organosulfurcompounds
H
H
HH
CH3
CH3
CH3
CH3CH3
HO
OH
HO
OHOH
MeO HOHO
OH OHPhloroglucinolPinostrobin
Hypericin
O
O
O
O
O
HO
OH
MeO
OH
O
O
OH
HO
O
O
OH
OH
OH
OH
NH2
OH
O
6-Gingerol
O
O
S
Allicin
S
S
S
Diallyl disulfide
S
Diallyl sulfide
S
S-allylcysteine
CH3
MeO
OH6-Paradol
O
CH3
Genistein
Kaempferol Quercetin
Daidzein
OH
HO
OH O
OOH
OHOH
Folienetriol
Soyasapogenol BOH
OH
HO
CH3CH3
CH3
H3C
H3C
HO
OHHO
St. John’swort
SaponinsPolysaccharidesFlavonoidsVolatile oils
Ginseng
IsoflavonesSaponinsSphingolipidsTrypsin inhibitors
Soy
Ginger
Garlic
HerbAgents/compounds Structures of some constituent molecules
OHOH O
Figure 1. Herbs, their active components, and structures of some constituent molecules.
Efficacy of Herbal Products in Colorectal Cancer Prevention Murillo et al. 37
Epidemiology and clinical evidenceEpidemiologic data support the protective role of gar-lic 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.
Experimental evidenceThe active components of garlic have been shown to medi-ate 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 carcinogene-sis. 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 carcinogene-sis [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 carcinogene-sis, 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 garlic’s 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].
GingerGinger 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 flavor-ing and as medicine. It is still commonly used for illnesses of the digestive system such as nausea from morning sickness or motion sickness.
Epidemiology and clinical evidenceNo human studies have been conducted to evaluate ginger’s CRC chemopreventive properties, but in vitro studies and studies in animals support its use for the pre-vention of colorectal cancer.
Experimental evidenceGinger’s active components have been reported to exhibit cancer-preventive activity in several experimental carcino-genesis 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 μM [17]. Zerumbone (50 μM) 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 hydro-peroxides, and conjugated dienes; antioxidant status was measured using superoxide dismutase, catalase, glutathi-one 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 antioxi-dant 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 gin-ger 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 glucu-
ronide 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 con-
tents. Animals receiving ginger during both the initiation and postinitiation periods had significantly fewer tumors than the controls. Furthermore, enzyme activity of muci-nase and -glucuronidase was significantly reduced in the tissues and fecal matter of rats receiving ginger as com-pared with control animals. These data suggest that ginger may protect against colon cancer by regulating the levels of intestinal microflora.
38 Prevention and Early Detection
In contrast, Dias et al. [20] failed to find a chemo-preventive 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 treat-ment, 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 possi-bility 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].
GinsengGinseng 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). His-torically, 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, polysac-charides, flavonoids, and volatile oils (Fig. 1) [21]. Cancer chemoprevention studies have largely examined the efficacy of ginseng ginsenosides.
Epidemiology and clinical evidenceSeveral 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 hospi-tal [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 non-consumers. The odds ratio of all cancer types in relation to ginseng consumption was 0.6 (95% CI, 0.5–0.7). Moreover, for CRC a decrease in risk was associated with a higher fre-quency 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 evalu-ate 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
cancer cases (58 people) was 0.3 (95% CI, 0.2–0.7) among consumers of fresh ginseng extract and 0.3 (95% CI, 0.1–0.7) 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 gin-seng tea for reducing the risk of cancer [23].
Experimental evidenceExperimental models have been instrumental in establish-ing 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]. Simi-larly, 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].
SoySoy 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 compo-nents of soy that have been investigated in relation to CRC are isoflavones (genistein and daidzein), saponins, sphingo-lipids, 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 con-sumed [28]. No dietary recommendations have been made for soy, but it has been suggested that up to 75 mg/d of iso-flavones (equivalent to a minimum of 25 g of soy protein) may be necessary for cancer prevention [28].
Epidemiology and clinical evidenceHistorically 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 [29–31]. A recent review summarized the association between soy con-sumption 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, investi-gations in animals and tissue culture have sought to better elucidate the role of soy and its active components in CRC.
Experimental evidenceFor 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) suppres-sion 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, Symo-lon et al. [33] examined the efficacy of soy sphingolipids against DMH-induced colon tumorigenesis in CF1 and APCMin/+ 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 APCMin/+ mice. Furthermore, the effects of dietary sphingolipids on gene expression in the intestinal mucosal cells of APCMin mice revealed downregulation of two transcription factors associated with cancer, hypoxia-induced 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 APCMin mice fed a Western-style (high-fat/low-fiber/low-calcium) diet contain-ing 16 to 475 mg/kg soy isoflavones. Others have reported enhanced induction of ACF, colon tumors, or both by vari-ous components of soy, including soy isoflavones [35] and purified genistein or genistein-rich soya protein [36]. Cumu-latively, 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 concor-dant 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.
St. John’s WortSt. John’s 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 bio-logically 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 proantho-cyanidins (Fig. 1) [38••]. Several of these active compounds have been reported to possess anticancer activities.
Epidemiology and clinical evidenceThere are no articles concerning the anticancer efficacy of SJW in humans.
Experimental evidenceExtracts of the plant H. perforatum have been used for centuries in traditional medicine, notably to treat depres-sion. 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 hypericin-induced photocytotoxicity has been investigated in colon cancer cells [39]. Sacková 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 hyperi-cin at increasing concentrations, and experiments were conducted on cell viability, cell number, cell cycle regula-tion, 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 antioxi-dant 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 [40–44].
40 Prevention and Early Detection
Tabl
e 2.
Evi
denc
e su
ppor
ting
the
effi
cacy
of h
erbs
aga
inst
col
orec
tal c
ance
r
Her
bIn
vit
ro s
tudi
es (c
ell l
ines
)A
nim
al s
tudi
es
Epid
emio
logi
c/cl
inic
al s
tudi
es
Type
No.
of s
tudi
esR
esul
t
Gar
licA
popt
osis
(Cac
o-2,
HT-
29, C
olo
205)
; in
crea
sed
casp
ase
3 ac
tivity
and
BA
X e
xpre
ssio
n (C
olo
205)
; G
1 ar
rest
(HT-
29, C
aco-
2);
upre
gula
tion
of p
21W
af1/
Cip
1 ;in
duct
ion
of h
isto
ne a
cety
latio
n (H
T-29
) [14
–16]
Gar
lic a
nd g
arlic
+ to
mat
o: d
ecre
ased
AC
F in
A
OM
-indu
ced
colo
n ca
ncer
in r
ats
[11]
Coh
ort [
9]3
All
supp
ortiv
e
Age
d ga
rlic
extr
act:
decr
ease
d D
MH
-indu
ced
colo
n tu
mor
s in
rat
s [1
2]C
ase-
cont
rol [
9]3
All
supp
ortiv
e
Dia
llyl s
ulfid
e: d
ecre
ased
form
atio
n of
AC
F in
A
OM
-indu
ced
colo
n ca
ncer
in r
ats;
dec
reas
ed
expr
essi
on o
f CO
X-2
and
iNO
S [1
3]
Pros
pect
ive
[10]
1G
arlic
sup
plem
ents
: no
ass
ocia
tion
Gin
ger
Apo
ptos
is (C
olo
205)
; gr
owth
inhi
bitio
n (L
S174
T, L
S180
, C
olo
205,
Col
o 32
0DM
) [17
]
Dec
reas
ed D
MH
-indu
ced
colo
n tu
mor
s in
rat
s [1
8]: d
ecre
ased
lipi
d pe
roxi
datio
n, in
crea
sed
antio
xida
nt a
ctiv
ity
No
stud
ies
avai
labl
e on
C
RC
pre
vent
ion
——
Dec
reas
ed D
MH
-ind
uced
col
on tu
mor
s in
ra
ts [1
9]: d
ecre
ased
muc
inas
e an
d -g
lucu
roni
dase
leve
ls
Gin
ger
mea
l die
t: no
dec
reas
e in
D
MH
-indu
ced
AC
F in
rat
s
Gin
seng
Apo
ptos
is, a
ntio
xida
nt (H
CT-
116)
[2
6,27
]Ko
rean
red
gin
seng
pow
der:
de
crea
sed
prog
ress
ion
of A
CF
[24]
Cas
e-co
ntro
l [22
]1
Supp
ortiv
e
Red
gins
eng:
dec
reas
ed A
CF
and
indu
ced
apop
tosi
s in
col
onic
cry
pts
[25]
Pros
pect
ive
[23]
1Su
ppor
tive
Soy
G2/
M a
rres
t (H
T-29
); in
hibi
tion
of c
dc2
kina
se, a
popt
osis
, inh
ibiti
on o
f DN
A
topo
isom
eras
e, in
hibi
tion
of ty
rosi
ne
kina
se (H
T-29
, Cac
o-2)
[37]
Soy
flour
: dec
reas
ed in
cide
nce
of A
CF
in
AO
M-in
duce
d co
lon
canc
er [3
2]Ec
olog
ical
3B
oth
ferm
ente
d an
d no
n-fe
rmen
ted
soy
prod
ucts
: pro
tect
ive
tren
d, b
ut c
onfid
ence
in
terv
als
over
lap
1.0
in m
ost s
tudi
es [
31]
Soy
sphi
ngol
ipid
s: in
hibi
ted
AC
F in
D
MH
-indu
ced
colo
n ca
ncer
in C
F1 m
ice;
in
hibi
ted
tum
ors
in A
PCM
in/+ m
ice
[33]
Cas
e-co
ntro
l9
Isofl
avon
es: d
ecre
ase,
enh
ance
, or
have
no
effe
ct o
n in
cide
nce
of A
CF
and
tum
ors
[34
–36]
Coh
ort
1
St. J
ohn’
s w
ort
Dec
reas
ed c
ell v
iabi
lity
(HT-
29);
G2/
M a
rres
t (C
aco-
2); a
popt
osis
(H
T-29
, Col
o 20
5) [3
9–4
4]
No
stud
ies
avai
labl
e on
CR
C p
reve
ntio
nN
o st
udie
s av
aila
ble
on
CR
C p
reve
ntio
n
——
AC
F—ab
erra
nt c
rypt
foci
; AO
M—
azox
ymet
hane
; CO
X-2
—cy
cloo
xyge
nase
-2; C
RC
—co
lore
ctal
can
cer;
DM
H—
1,2-
dim
ethy
lhyd
razi
ne; i
NO
S—in
duci
ble
nitr
ic o
xide
syn
thas
e.
Efficacy of Herbal Products in Colorectal Cancer Prevention Murillo et al. 41
ConclusionsA 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 demonstrat-ing 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. Further-more, 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 combina-tion 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 dif-ference 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 high-risk individuals. Studies elucidating their mechanisms of action will help to determine which specific conditions and populations will benefit most from their consumption.
DisclosuresNo potential conflict of interest relevant to this article was reported.
References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as• Of importance•• Of major importance
1.•• Gurib-Fakim A: Medicinal plants: traditions of yesterday and drugs of tomorrow [review]. Mol Aspects Med 2006, 27:1–93.
This paper provides an overview of the different classes of molecules present in plants and presents data on the use of plant products in the development of functional foods, addresses the needs for validation of plant extracts, and discusses the safety, efficacy, and quality of phytomedications.2. Tapsell LC, Hemphill I, Cobiac L: Health benefits of herbs
and spices: the past, the present, the future. Med J Aust 2006, 185:S4–S24.
3. Gardiner P, Graham R, Legedza AT, et al.: Factors associ-ated with herbal therapy use by adults in the United States. Altern Ther Health Med 2007, 13:22–29.
4. Jemal A, Siegel R, Ward E, et al.: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43–66.
5. Saydah SH, Eberhardt MS: Use of complementary and alternative medicine among adults with chronic diseases: United States 2002. J Altern Complement Med 2006, 12:805–812.
6. Tindle HA, Davis RB, Phillips RS, Eisenberg DM: Trends in use of complementary and alternative medicine by US adults: 1997–2002. Altern Ther Health Med 2005, 11:42–49.
7. Ernst E: The efficacy of herbal medicine—an overview. Fundam Clin Pharmacol 2005, 19:405–409.
8. Shukla Y, Kalra N: Cancer chemoprevention with garlic and its constituents. Cancer Lett 2007, 247:167–181.
9. Dorant E, van den Brandt PA, Goldbohm RA, et al.: Garlic and its significance for the prevention of cancer in humans: a critical view. Br J Cancer 1993, 67:424–429.
10. Fleischauer AT, Arab L: Garlic and cancer: a critical review of the epidemiologic literature. J Nutr 2001, 131:1032S–1040S.
11. Sengupta A, Ghosh S, Das S: Tomato and garlic can modulate azoxymethane-induced colon carcinogenesis in rats. Eur J Cancer Prev 2003, 12:195–200.
12. Katsuki T, Hirata K, Ishikawa H, et al.: Aged garlic extract has chemopreventive effects on 1,2-dimethylhydrazine-induced colon tumors in rats. J Nutr 2006, 136:847S–851S.
13. Sengupta A, Ghosh S, Das RK, et al.: Chemopreventive potential of diallylsulfide, lycopene and theaflavin during chemically induced colon carcinogenesis in rat colon through modulation of cyclooxygenase-2 and inducible nitric oxide synthase pathways. Eur J Cancer Prev 2006, 15:301–305.
14. Jakubíková J, Sedlák J: Garlic-derived organosulfides induce cytotoxicity, apoptosis, cell cycle arrest, and oxida-tive stress in human colon carcinoma cell lines. Neoplasma 2006, 53:191–199.
15. Su CC, Chen GW, Tan TW, et al.: Crude extract of garlic induced caspase-3 gene expression leading to apoptosis in human colon cancer cells. In Vivo 2006, 20:85–90.
16. Druesne N, Pagniez A, Mayeur C, et al.: Diallyl disulfide (DADS) increases histone acetylation and p21 (waf1/cip1) expression in human colon tumor cell lines. Carcinogenesis 2004, 25:1227–1236.
17. Murakami A, Takahashi D, Kinoshita T, et al.: Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the
, -unsaturated carbonyl group is a prerequisite. Carcino-genesis 2002, 23:795–802.
18. Manju V, Nalini N: Chemopreventive efficacy of ginger, a naturally occurring anticarcinogen during the initiation, post-initiation stages of 1,2 dimethylhydrazine-induced colon cancer. Clinica Chimica Acta 2005, 358:60–67.
19. Manju V, Nalini: Effect of ginger on bacterial enzymes in 1,2-dimethylhydrazine-induced experimental colon carcinogenesis. Eur J Cancer Prev 2006, 15:377–383.
20. Dias MC, Spinardi-Barbisan AL, Rodrigues MA, et al.: Lack of chemopreventive effects of ginger on colon carcino-genesis induced by 1,2-dimethylhydrazine in rats. Food Chem Toxicol 2006, 44:877–884.
21. Shin HR, Kim JY, Yun TK, et al.: The cancer-preventive potential of Panax ginseng: a review of human and experi-mental evidence. Cancer Causes Control 2000, 11:565–576.
22. Yun TK, Choi SY: A case-control study of ginseng intake and cancer. Int J Epidemiol 1999, 19:871–876.
23. Yun TK, Choi SY: Preventive effect of ginseng intake against various human cancers: a case-control study on 1987 pairs. Cancer Epidemiol Biomarkers Prev 1995, 4:401–408.
24. Wargovich MJ: Colon cancer chemoprevention with ginseng and other botanicals. J Korean Med Sci 2001, 16(Suppl):S81–S86.
25. Volate SR, Davenport DM, Muga SJ, Wargovich MJ: Modu-lation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis 2005, 26:1450–1456.
42 Prevention and Early Detection
26. Wang CZ, Luo X, Zhang B, et al.: Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells. Cancer Chemother Pharmacol 2007, 60:69–79.
27. Helms S: Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev 2004, 9:259–274.
28. Messina M, Nagata C, Wu AH: Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer 2006, 55:1–12.
29. Toyomura K, Kono S: Soybeans, soy foods, isoflavones and risk of colorectal cancer: a review of experimental and epide-miological data. Asian Pac J Cancer Prev 2002, 3:125–132.
30. Oba S, Nagata C, Shimizu N, et al.: Soy product consump-tion and the risk of colon cancer: a prospective study in Takayama, Japan. Nutr Cancer 2007, 57:151–157.
31. Spector D, Anthony M, Alexander D, Arab L: Soy consump-tion and colorectal cancer. Nutr Cancer 2003, 47:1–12.
32. Murillo G, Choi JK, Pan O, et al.: Efficacy of garbanzo flour in suppression of aberrant crypt foci in the colons of CF-1 mice. Anticancer Res 2004, 24:3049–3055.
33. Symolon H, Schmelz EM, Dillehay D, Merrill AH Jr: Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and APCMin/+
mice. J Nutr 2004, 134:1157–1161.34. Sørensen IK, Kristiansen E, Mortensen A, et al.: The effect
of soy isoflavones on the development of intestinal neoplasia in ApcMin mouse. Cancer Lett 1998, 130:217–225.
35. Daly KT, Tracy AC, Malik M, et al.: Enhanced estrogenic responses and sensitivity to azoxymethane following dietary soy isoflavone supplementation in older female rats. Food Chem Toxicol 2007, 45:628–637.
37. Gee JM, Noteborn HP, Polley AC, Johnson IT: Increased induction of aberrant crypt foci by 1,2-dimethylhydrazine in rats fed diets containing purified genistein or genistein-rich soya protein. Carcinogenesis 2000, 21:2255–2259.
38.•• Lechner D, Kallay E, Cross HS: Phytoestrogens and colo-rectal cancer prevention. Vitam Horm 2005, 70:169–198.
This is a comprehensive review of a variety of studies exploring possible relations between phytoestrogen uptake and CRC risk.
39. Scwarz D, Kisselev P, Roots I: St. John’s wort extracts and some of their constituents potently inhibit ultimate carcinogen formation from benzo[ ]pyrene-7,8-dihydrodiol by human CYP1A1. Cancer Res 2003, 63:8062–8068.
40. Sacková V, Fedorocko P, Szilárdiová B, et al.: Hypericin-induced photocytotoxicity is connected with G2/M arrest in HT-29 and S-phase arrest in U937 cells. Photochem Photobiol 2006, 82:1285–1291.
41. Tedeschi E, Menegazzi M, Margotto D, et al.: Anti-inflamma-tory actions of St. John’s wort: inhibition of human inducible nitric-oxide synthase expression by down-regulating signal transducer and activator of transcription-1 (STAT-1 )activation. J Pharmacol Exp Ther 2003, 307:254–261.
42. Tian R, Koyabu N, Morimoto S, et al.: Functional induction and de-induction of P-glycoprotein by St. John’s wort and its ingredients in a human colon adenocarcinoma cell line. Drug Metab Dispos 2005, 33:547–554.
43. Kim WK, Bang MH, Kim ES, et al.: Quercetin decreases the expression of Erb2 and Erb3 proteins in HT-29 human colon cancer cells. J Nutr Biochem 2005, 16:155–162.
44. Yang K, Lamprecht SA, Liu Y, et al.: Chemoprevention studies of the flavonoids quercetin and rutin in normal and azoxymethane-treated mouse colon. Carcinogenesis 2000, 21:1655–1660.
45. Turini ME, DuBois RN: Primary prevention: phytopreven-tion and chemoprevention of colorectal cancer. Hematol Oncol Clin N Am 2002, 16:811–840.
46. Johnson JJ, Mukhtar H: Curcumin for chemoprevention of colon cancer. Cancer Lett 2007, 255:170–181.
47. Aggarwal BB, Bhardwaj A, Aggarwal RS, et al.: Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 2004, 24:2783–2840.