Online Submissions: http://www.journaltcm.
com J Tradit Chin Med 2016 April 15; 36(2): 243-249
info@journaltcm.com
Therapeutic targets of Traditional Chinese Medicine for colorectal
cancer
Li Weidong, Li Chunsheng, Zheng Honggang, Chen Guohong, Hua Baojin
aa
Li Weidong, Zheng Honggang, Hua Baojin, Oncology De-
partment, Guang'anmen Hospital, China Academy of Chi-
nese Medical Sciences, Beijing 100053, China
Li Chunsheng, Nephrology department, Taizhou Central
Hospital, Taizhou 318000, China
Chen Guohong, Urinary surgery Department, Guang'an-
men Hospital, China Academy of Chinese Medical Sciences,
Beijing 100053, China
Supported by National Natural Science Foundation of Chi-
na (Research for the Mechanism of Fei-Liu-Ping Ointment
Regulating Tumor Inflammatory Microenvironment to Pre-
vent Lung Cancer Metastasis, No. 81273718); China Postdoc-
toral Science Foundation (In vitro study on Fei-Liu-Ping oint-
ment preventing lung cancer metastasis caused by inflam-
matory microenvironment, No. 2012T50199)
Correspondence to: Dr. Hua Baojin, Oncology Depart-
ment, Guang'anmen Hospital, China Academy of Chinese
Medical Sciences, Beijing 100053, China. dr.huabaojin@hot-
mail.com; Dr. Chen Guohong, Urinary surgery Department,
Guang'anmen Hospital, China Academy of Chinese Medical
Sciences, Beijing 100053, China. cghdoctor@sina.com
Telephone: +86-10-88001221.
Accepted: August 20, 2015
Abstract
OBJECTIVE: To explore the role of Traditional Chi-
nese Medicine (TCM) in the prevention and treat-
ment of colorectal cancer and identify possible
therapeutic targets of TCM to provide clues for the
use of TCM for colorectal cancer prevention and
treatment in the clinic and to find novel directions
for new drug discovery for colorectal cancer.
METHODS: We used PubMed and Google to search
for and collect scientific publications for a full evalu-
ation of current evidence in the literature indicat-
ing the potential role of Chinese herbal medicines
JTCM | www. journaltcm. com
ISSN 0255-2922
© 2016 JTCM. All rights reserved.
REVIEW
TOPIC
and their respective ingredients as effective candi-
dates for colorectal cancer prevention and treatment.
RESULTS: We extracted a detailed description of
potential therapeutic Chinese herbal medicines
and their constituent ingredients that target differ-
ent mechanisms in colorectal cancer such as gene
mutation, dysregulation of signaling pathways, me-
tabolism disorders, and the inflammatory microen-
vironment, including both conventional and
non-conventional approaches.
CONCLUSION: TCM may be a promising comple-
mentary and alternative therapy for the treatment
of colorectal cancer.
© 2016 JTCM. All rights reserved.
Key words: Colorectal neoplasms; Medicine, Chi-
nese traditional; Prevention and control; Therapeu-
tics; Drug delivery systems
INTRODUCTION
Colorectal cancer is a serious and fatal disease. Al-
though the specific pathogenetic mechanism is not ful-
ly proven, it is generally accepted that the risk factors
for colorectal cancer include a genetic component,
such as gene mutations, and an environmental compo-
nent, such as a high-fat diet.1 Current clinical treat-
ment of colorectal cancer mainly focuses on the use of
radiation therapy and chemotherapy. However, as
long-term use of these therapies causes serious side ef-
fects there is a need to find alternative therapies with
high efficacy but few side effects. Use of Traditional
Chinese Medicine (TCM) is an attractive approach for
the prevention and treatment of colorectal cancer
worldwide.2
243 April 15, 2016 | Volume 36 | Issue 21 |
 Li WD et al. / Review
This paper focuses on the pathogenesis of colorectal
cancer and the efficacy of Chinese medicine in prevent-
ing and treating cancer with the aim of identifying pos-
sible therapeutic targets of Chinese herbal medicine
that might be beneficial in the prevention and treat-
ment of colorectal cancer.
METHODS
We searched PubMed and Google online up to July
2014 to find papers focusing on colorectal cancer pre-
vention and treatment to evaluate current evidence in
the literature indicating the potential role of Chinese
herbal medicines and their respective ingredients as ef-
fective candidates for colorectal cancer prevention and
treatment. The search terms used were: "Traditional
Chinese Medicine" or "Chinese Herbal Medicine" and
"Colon Cancer". Reference lists of the retrieved articles
were also reviewed for additional relevant studies.
RESULTS
Targeting kras and apc mutation in colorectal cancer
with TCM
Sporadic colorectal cancer in humans is caused by
long-term accumulation of multiple somatic mutations
in various genes, including oncogenes, tumor suppres-
sor genes, and epigenetic genes. The three routes of
cancer associated with genomic instability are chromo-
somal genomic instability (CIN), microsatellite insta-
bility, and a CpG island methylation phenotype
(CIMP). CIN is one of the main causative factors of
colon cancer (present in 80%-85% of cases), and is
closely related to the malignant progression of colorec-
tal cancer.3 CIN combined with mutation or inactiva-
tion of the adenomatous polyposis coli (APC) gene
and functional mutations in the β-catenin gene (CTN-
NB1) can lead to the formation of early intestinal ade-
nocarcinoma. Somatic APC mutation is present in ap-
proximately 90% of sporadic colorectal cancer tumor
tissues and can lead to constitutive β-catenin activation
and the subsequent activation of many genes involved
in the induction of tumorigenesis, such as c-myc.
Kras mutations in colorectal cancer patients are linked
to the patient's life span, tumor progression, and che-
motherapy resistance.4 In addition, Kras mutation com-
bined with APC loss synergistically increases Wnt sig-
naling, thus contributing to tumor growth and inva-
sion.5 The presence of a Kras mutation in a patient
with colorectal cancer therefore makes the disease hard-
er to treat.
Numerous studies have shown that Chinese herbal
medicine has a definite effect on colorectal cancer
through the regulation of gene expression. Resveratrol,
a major ingredient of Huzhanggen (Radix Polygoni Cus-
pidati), can induce colorectal cancer cell apoptosis,6 in-
hibit cell proliferation,7,8 and inhibit APCmin intestinal
JTCM | www. journaltcm. com
tumor formation in mice.9 These chemopreventive
roles of resveratrol and other active ingredients in herb-
al medicines can be partially reflected by post-transcrip-
tional regulation and epigenetic modifications.10,11 For
example, resveratrol has been shown to increase the ex-
pression of miRNA-622 in colorectal cancer cells while
inhibiting the expression of Kras.12
Berberine, a main ingredient in Huanglian (Rhizoma
Coptidis), downregulates c-myc expression and increas-
es APC gene expression, thus interfering with
β-catenin nuclear translocation; in addition, berberine
intervention in APCMin/+ mice leads to smaller intestinal
tumor size and a decreased number of tumors through
inhibition of the Wnt / β-catenin signal.13
Colorectal cancer gene mutations are mainly concen-
trated in APC, Kras, and certain other genes, and such
mutations are considered the ultimate targets for block-
ing tumor angiogenesis and tumor cell proliferation
through the Wnt / β-catenin signal pathway. If TCM
or its single constituents could regulate downstream tar-
gets of β-catenin, it might be a perfect candidate for in-
hibition of the progression of colorectal cancer.
Targeting metabolism disorders in colorectal cancer
with TCM
Colorectal cancer is known to be associated with a
high-fat diet and colorectal metabolism disorders. Epi-
demiologic studies found that the incidence of colorec-
tal cancer and mortality rates vary geographically.14-16
There is evidence that diet and nutritional factors play
key roles in the onset and progression of colorectal can-
cer;17-20 consumption of a high-fat diet and genetic risk
factors can induce an energy imbalance and increase
the incidence of colorectal cancer.21-25 In ApcMin/+ mice, a
spontaneous increase in the number of intestinal tu-
mors is associated with a high-fat diet.26
AMP-activated protein kinase (AMPK) is one of the
key sensors for regulation of energy metabolism and is
also a key factor in the regulation of cell growth and
apoptosis.27-29 Once activated, AMPK can phosphory-
late many metabolic enzymes, inhibit the signaling
pathways of ATP consumption, and increase fatty acid
oxidation.30,31
Many flavonoids extracted from Chinese herbal medi-
cines, such as wogonin,32 tanshinone ⅡA,33 quercetin,34,35
and cryptotanshinone,36 can induce AMPK activation,
which then inhibits proliferation and induces apoptosis
of cancer cells.37 Therefore, selected pharmaceutical in-
gredients from TCM that target the activation of
AMPK may be helpful for colorectal cancer prevention
and treatment. There are more than 20 types of Chi-
nese herbal medicine that can be used for metabolic
disorders, and their main mechanisms of action are reg-
ulation of mitochondrial function and glucose metabo-
lism and stimulation of AMPK activation.38-40 Berber-
ine, an alkaloid from TCM, can significantly inhibit
colorectal cancer proliferation and tumor formation
through activation of AMPK.41
244 April 15, 2016 | Volume 36 | Issue 21 |
 Li WD et al. / Review
Targeting key signaling pathways related to
colorectal cancer with TCM
Signaling pathways that are closely associated with the
incidence of colorectal cancer include Signal Transduc-
er and Activator of Transcription-3 (Stat3), Wnt, Mito-
gen-activated protein kinases (MAPK), and p53 path-
ways (Table 1); targeting the regulation of these path-
ways is an important approach to find effective antican-
cer candidates in TCM.
Stat3 signal pathway and colorectal cancer
Activation of Signal Transducer and Activator of Tran-
scription-3 (Stat3) is prevalent in tumor cells and in-
duces the expression a large number of genes involved
in tumor formation. Stat3 is an important target for
the prevention and treatment for colorectal cancer.52
Stat3 activation is negatively correlated with clinical an-
titumor results.53 Sustained Stat3 activation can affect
multiple levels of malignant change,54 including the in-
duction of cell cycle regulators, uncontrolled prolifera-
tion of cancer cells induced by cyclin D1 and c-myc,
and the induction of different antiapoptotic proteins
such as Bcl-2, Mcl-1, and Survivin for escape from
apoptosis. Stat3 activation also regulates proteins in-
volved in cancer invasion, metastasis, and angiogene-
sis.55 The role of Stat3 in the regulation of many genes
during carcinogenesis makes it a promising target for
cancer treatment.56
Many TCMs and their single components with
heat-clearing and detoxifying roles can significantly in-
hibit proliferation and induce apoptosis of colon can-
Table 1 Targeting of signaling pathways in colorectal cancer by TCM
Botanical or chemical name Targeted signal pathway
Huanglian (Rhizoma Coptidis)13,41 Wnt/β-catenin
AMPK
Yujin (Radix Curcumae Wenyujin)42 MAPK
Baihuasheshecao (Herba Hedyotdis)43,44 sonic hedgehog, Stat3,
Akt and p70S6K
Huanglian (Rhizoma Coptidis)13,41 Wnt/β-catenin
Jianghuang (Rhizoma Curcumae Longae) 45
NF-κB/PI-3K/Src path-
ways
Banmao (Mylabris Plalerata)46 p38 MAPK and Akt
Banzhilian (Herba Scutellariae Barbatae) 47
Akt and p53 pathways
Huangqi (Radix Astragali Mongolici)48 mTOR signaling
and Erk signaling
Houpu (Cortex Magnoliae Officinalis)49 Notch signaling
Renshen (Radix Ginseng)50 Wnt/β-catenin
Fangji (Radix Stephaniae Tetrandrae)51 Wnt/β-catenin
Notes: MAPK: mitogen-activated protein kinases; Stat3: signal transducer and activator of transcription-3; AKT: protein kinase B;
p70S6K: ribosomal protein S6 kinase; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappaB; AMPK: Adenosine 5′-mo-
nophosphate (AMP)-activated protein kinase; PI-3K: phosphatidylinositol 3-kinase; Src: sarcoma gene; Erk: extracellular regulated protein
kinases.
JTCM | www. journaltcm. com 245
cer cells through regulation of the Stat3 signaling path-
way. Banzhilian (Herba Scutellariae Barbatae) can sup-
press the activation of Stat3 in colorectal cancer and
subsequently inhibit its downstream targets that are
linked to colon cancer cell proliferation and apopto-
sis.57 Quinazoline alkaloid, extracted from bitter beans,
can inhibit colon cancer cell proliferation and apopto-
sis through inhibition of Jak / Stat3 and PI-3K / AKT
signaling pathways.58 Xiakucao (Spica Prunellae Vulgar-
is) inhibits the proliferation of colorectal cancer cells,
induces apoptosis, and inhibits angiogenesis in colorec-
tal cancer tissue by inhibiting the phosphorylation of
Stat3.59 Experiments in tumor-bearing animals show
that Pientzehuang reduces tumor mass, accompanied
by inhibition of the phosphorylation of Stat3 in tumor
tissue.60
Wnt signal pathway and colorectal cancer
The Wnt pathway plays a leading role in the initiation
and progression of colorectal cancer.61 Although there
is a clear correlation between Wnt signaling and
colorectal cancer, drugs targeting this pathways are lim-
ited62 and it is necessary to find candidates targeting
downstream proteins of the Wnt signaling pathway, es-
pecially APC, AXIN2 (Axis inhibition protein 2), or
β-catenin. Therefore, it is important to search TCM
for candidates that can target the Wnt signaling path-
way for the prevention and treatment of colorectal cancer.
Tetrandra, extracted from Fangji (Radix Stephaniae Tet-
randrae), can inhibit the growth of colorectal tumors
and suppress cell proliferation through inhibition of
Activity In vitro or in vivo
Inhibits colon tumor formation In vivo
Inhibits colon tumor formation and
In vitro and in vivo
induces apoptosis
Inhibits proliferation and induces In vitro
apoptosis
Inhibition of tumor angiogenesis In vitro and in vivo
Inhibits colon tumor formation In vivo
Inhibition of IκBα kinase activation In vitro
and IκBα phosphorylation
Inhibitor of tumor angiogenesis In vitro and in vivo
Inhibits proliferation and induces G1/ In vitro
S arrest
Suppresses angiogenesis In vitro and in vivo
Inhibits colon cancer growth In vitro and in vivo
Blocks the nuclear translocation of In vitro
β-catenin
Inhibits proliferation, viability, and xe- In vitro and in vivo
nograft tumor growth
April 15, 2016 | Volume 36 | Issue 21 |
 Li WD et al. / Review
Table 2 Chinese herbals and their extracts that target the inflammatory microenvironment of colorectal cancer in vivo
Family and botanical name Part used
Huanglian (Rhizoma Coptidis)41 Root
Huangqin
Root
(Radix Scutellariae Baicalensis)70,71
Root
Danshen (Radix Salviae Miltiorrhizae)72 Root
Juhua (Flos Chrysanthemi)73 Flower
Yiyiren (Semen Coicis)74 Fruit
Huangqi (Radix Astragali Mongolici)75 Root
Juemingzi (Semen Cassiae Obtusifoliae) 76
Fruit
Roucongrong
Stem
(Herba Cistanches Deserticolae)77
Notes: AOM: azoxymethane; DSS: dextran sulfate sodium.
β-catenin.51 Resveratrol has been found to inhibit the
proliferation of colon cancer cells and induce apoptosis
in vitro and in vivo in association with inhibition of
β-catenin.63 Saud et al 64 found that isorhamnetin, a
chemical component of Puhuang (Pollen Typhae), pre-
vents colorectal tumor formation in mice by inhibiting
c-Src activation and the subsequent transcriptional acti-
vation of β-catenin.
MAPK signal pathway and colorectal cancer
Mammals possess three parallel MAPK signaling path-
ways: ERK1/2, JNK, and p38MAPK pathways. Of
these, the ERK1/2 signaling pathway is the key path-
way contributing to the survival and proliferation of tu-
mors, therefore targeting the ERK1/2 signaling path-
way by TCM is critical for colorectal cancer prevention
and treatment.
Evodiamine, an active ingredient of Wuzhuyu (Fructus
Evodiae Rutaecarpae), induces colorectal cancer cell
apoptosis by activating the JNK signaling pathway.65
Triptolide, a main ingredient of Tripterygium, inhibits
colon cancer cell viability and the cell cycle through
phosphorylation of ERK1/2 and AKT.66 Quercetin, a
major ingredient of Apocynum leaf extract, can regu-
late multiple signaling pathways including MEK/ERK
and Nrf/Keap1 signaling pathways.67 An active ingredi-
ent in magnolia extract, honokiol, enhances cell sensi-
tivity to oxaliplatin treatment while increasing the rate
of apoptosis and inhibiting growth of cancer cells
through phosphorylation of ERK1/2 and AKT.68
Based on abnormal signaling pathways, identification
of related upstream and downstream target genes
through genetic screening in patients and selection of
effective ingredients from TCM that block the mutant
target genes and proteins is a good approach to colorec-
tal cancer treatment.
Targeting the inflammatory microenviroment of
colorectal cancer with TCM
Inflammatory bowel diseases (IBD), including ulcer-
JTCM | www. journaltcm. com
Extract Model Mammal tested
AOM/DSS-
Berberine Mouse
induced colorectal carcinogenesis
AOM/DSS-
Wogonin Mouse
induced colorectal carcinogenesis
AOM/DSS-
Baicalein Mouse
induced colorectal carcinogenesis
AOM/DSS-
Salvia Mouse
induced colorectal carcinogenesis
AOM/DSS-
Digitoflavone Mouse
induced colorectal carcinogenesis
AOM/DSS-
Adlay Rat
induced colorectal carcinogenesis
Astragalus Saponins Colorectal xenograft Mouse
H2O Extract Colorectal xenograft Mouse
H2O Extract Helicobacter infection Mouse
ative colitis and Crohn's disease, are linked to the inci-
dence of colorectal cancer.69 Therefore, treatment of in-
flammatory bowel disease is an important approach in
the prevention and treatment of colorectal cancer. Re-
cent results show that many herbal medicines have du-
al roles as anti-inflammatory and antitumor agents (Ta-
ble 2).
Baicalein, the main ingredient of Huangqin, can inhib-
it colorectal cancer in vivo and in vitro by inhibiting
NF-κB activation to reduce the number of intestinal
tumors.71 Salvia extract can significantly alleviate the
symptoms of intestinal inflammation and serves as a
better candidate for colitis-associated carcinogenesis.72
The extract of Houttuynia inhibits colorectal cancer
cell growth and induces apoptosis through inhibition
of mitochondrial enzymes.78 TCMs that are currently
in use as anti-inflammatory agents should not be limit-
ed to one kind of disease; their anti-inflammatory prop-
erties may also be beneficial for colitis-associated carci-
nogenesis.
DISCUSSION
Based on the above analysis, we found that both Chi-
nese medicines and their constituent compounds with
multiple targets were promising candidates for colorec-
tal cancer prevention and treatment. The development
of colorectal cancer is a chronic multi-step process, and
TCMs with different characteristics could be used to
target different stages of colorectal cancer progression.
Herbals with anti-inflammatory properties can be used
at earlier stages of colorectal cancer progression for ear-
ly prevention to reduce inflammatory symptoms, and
even tumor formation, of colorectal cancer. Moreover,
TCM may be combined with chemical drugs to allevi-
ate the inflammatory intestinal microenvironment to
delay the tumor burden. These notions suggest that we
should be focused on clinical early intervention and
246 April 15, 2016 | Volume 36 | Issue 21 |
 Li WD et al. / Review
prevention, especially for patients who have inflamma-
tory bowel disease. Using TCM with anti-inflammato-
ry properties at an earlier time may be beneficial for
both reducing the inflammatory bowel disease and
blocking further progression of the colorectal cancer, as
reflected in the concepts emphasized by TCM of "pre-
vention before disease and anti-transformation after dis-
ease."
In addition, we found that both TCM and its single
constituents have multiple targets, which is totally dif-
ferent from chemical therapies with only a single tar-
get. This suggests that we can detect genes involved in
intestinal metabolism by screening different cancer pa-
tients, and then select specific gene-targeted herbal
medicines for their treatment. For example, herbal
medicines that promote blood circulation may have a
stronger effect on the Stat3 signaling pathway for
colorectal cancer treatment, whereas Chinese herbals
with heat clearing and dampness drying characters may
have a stronger effect on the Wnt signaling pathway or
the inflammatory NF-кB signaling pathway for
colorectal cancer treatment. Chinese herbal medicines
with multiple targets may be the best choice for
colorectal cancer prevention and treatment.
We can select Chinese herbal medicines that regulate
tumor metabolism for clinical intervention in accor-
dance with their specific characteristics. For example,
Chinese medicine monomers and compounds that can
activate AMPK have some similarities and can all be
used for the treatment of diabetes and other metabolic
disorders; this suggests that we may find new drugs
and effective ingredients for colorectal cancer preven-
tion and treatment among this kind of Chinese herbal
medicine.
The inflammatory microenvironment plays a key role
in multiple processes during the progression of colon
cancer. This provides us with the opportunity to find
effective therapeutic compounds from herbal medi-
cines with anti-inflammatory characteristics. We
should explore effective compounds from TCM for
colorectal cancer treatment based on our knowledge of
the characteristics, taste, and meridians of these Chi-
nese herbal medicines. We should also consider the ris-
ing, falling, floating, sinking and other features of the
herbal medicine for colorectal cancer prevention and
treatment, rather than depending only on its anti-in-
flammatory properties.
The development and progression of colorectal cancer
is a complex process involving multiple links and mech-
anisms that cannot be targeted by a single medicinal
drug against a single target. Rather, we should consider
integration of the different characteristics of Chinese
medicines to compose one prescription with multiple
targets for the prevention and treatment of colorectal
cancer. Finding effective candidates for colorectal can-
cer treatment among TCMs should be based on combi-
nation of the concepts of "treatment based on the over-
all" and "treatment based on syndrome differentia-
JTCM | www. journaltcm. com
tion", and the consideration of "local symptoms" and
"global symptoms" of the patients. Moreover, we
should aim to use TCM to maximize clinical efficiency
while minimizing toxicities for optimal prevention and
treatment of colorectal cancer.
REFERENCES
1 Lieberman DA, Prindiville S, Weiss DG, Willett W,
Group VACS. Risk factors for advanced colonic neoplasia
and hyperplastic polyps in asymptomatic individuals. JA-
MA 2003; 290(22): 2959-2967.
2 Stiefelhagen P. Prevention of colon carcinoma. Can herb-
al medicine prevent colon cancer? MMW Fortschr Med
2012; 154(9): 24.
3 Grady WM, Carethers JM. Genomic and epigenetic insta-
bility in colorectal cancer pathogenesis. Gastroenterology
2008; 135(4): 1079-1099.
4 Kinzler KW, Vogelstein B. Lessons from hereditary
colorectal cancer. Cell 1996; 87(2): 159-170.
5 Janssen KP, Alberici P, Fsihi H, et al. Apc and oncogenic
kras are synergistic in enhancing wnt signaling in intesti-
nal tumor formation and progression. Gastroenterology
2006; 131 (4): 1096-1109.
6 Liang YC, Tsai SH, Chen L, Lin-Shiau SY, Lin JK. Resve-
ratrol-induced g2 arrest through the inhibition of cdk7
and p34cdc2 kinases in colon carcinoma ht29 cells. Bio-
chem Pharmacol 2003; 65(7): 1053-1060.
7 Juan ME, Wenzel U, Daniel H, Planas JM. Resveratrol in-
duces apoptosis through ros-dependent mitochondria
pathway in ht-29 human colorectal carcinoma cells. J Ag-
ric Food Chem 2008; 56(12): 4813-4818.
8 Fuggetta MP, Lanzilli G, Tricarico M, et al. Effect of resve-
ratrol on proliferation and telomerase activity of human
colon cancer cells in vitro. J Exp Clin Cancer Res 2006; 25
(2): 189-193.
9 Schneider Y, Duranton B, Gosse F, Schleiffer R, Seiler N,
Raul F. Resveratrol inhibits intestinal tumorigenesis and
modulates host-defense-related gene expression in an ani-
mal model of human familial adenomatous polyposis. Nu-
tr Cancer 2001; 39(1): 102-107.
10 Ross SA. Diet and DNA methylation interactions in can-
cer prevention. Ann N Y Acad Sci 2003; 983: 197-207.
11 Ross SA, Dwyer J, Umar A, et al. Introduction: Diet, epi-
genetic events and cancer prevention. Nutr Rev 2008; 66
Suppl 1: S1-S6.
12 Han Z, Yang Q, Liu B, et al. Microrna-622 functions as a
tumor suppressor by targeting k-ras and enhancing the an-
ticarcinogenic effect of resveratrol. Carcinogenesis 2012;
33(1): 131-139.
13 Zhang J, Cao H, Zhang B, et al. Berberine potently atten-
uates intestinal polyps growth in apcmin mice and familial
adenomatous polyposis patients through inhibition of wnt
signalling. J Cell Mol Med 2013; 17(11): 1484-1493.
14 O'Keefe SJ, Kidd M, Espitalier-Noel G, Owira P. Rarity
of colon cancer in africans is associated with low animal
product consumption, not fiber. Am J Gastroenterol
1999; 94(5): 1373-1380.
15 Kono S. Secular trend of colon cancer incidence and mor-
tality in relation to fat and meat intake in japan. Eur J
247 April 15, 2016 | Volume 36 | Issue 21 |
 Li WD et al. / Review
Cancer Prev 2004; 13(2): 127-132.
16 Hill MJ. Bile flow and colon cancer. Mutat Res 1990; 238
(3): 313-320.
17 Hill-Baskin AE, Markiewski MM, Buchner DA, et al. Di-
et-induced hepatocellular carcinoma in genetically predis-
posed mice. Hum Mol Genet 2009; 18(16): 2975-2988.
18 Aune D, Chan DS, Lau R, et al. Dietary fibre, whole
grains, and risk of colorectal cancer: systematic review and
dose-response Meta-analysis of prospective studies. BMJ
2011; 343: d6617.
19 Vargas AJ, Thompson PA. Diet and nutrient factors in
colorectal cancer risk. Nutr Clin Pract 2012; 27(5):
613-623.
20 Meyerhardt JA, Sato K, Niedzwiecki D, et al. Dietary gly-
cemic load and cancer recurrence and survival in patients
with stage Ⅲ colon cancer: findings from calgb 89803. J
Natl Cancer Inst 2012; 104(22): 1702-1711.
21 Giovannucci E, Goldin B. The role of fat, fatty acids, and
total energy intake in the etiology of human colon cancer.
Am J Clin Nutr. 1997; 66(6 Suppl): 1564S-1571S.
22 Kim YS, Milner JA. Dietary modulation of colon cancer
risk. J Nutr 2007; 137(11 Suppl): 2576S-2579S.
23 Calle EE, Thun MJ. Obesity and cancer. Oncogene 2004;
23(38): 6365-6378.
24 Johnson IT, Lund EK. Review article: nutrition, obesity
and colorectal cancer. Aliment Pharmacol Ther 2007; 26
(2): 161-181.
25 Frezza EE, Wachtel MS, Chiriva-Internati M. Influence
of obesity on the risk of developing colon cancer. Gut
2006; 55(2): 285-291.
26 Van Kranen HJ, van Iersel PW, Rijnkels JM, et al. Effects
of dietary fat and a vegetable-fruit mixture on the develop-
ment of intestinal neoplasia in the apcmin mouse. Carci-
nogenesis 1998; 19(9): 1597-1601.
27 Hayashi T, Hirshman MF, Fujii N, et al. Metabolic stress
and altered glucose transport: Activation of amp-activated
protein kinase as a unifying coupling mechanism. Diabe-
tes 2000; 49(4): 527-531.
28 Terai K, Hiramoto Y, Masaki M, et al. Amp-activated pro-
tein kinase protects cardiomyocytes against hypoxic injury
through attenuation of endoplasmic reticulum stress. Mol
Cell Biol 2005; 25(21): 9554-9575.
29 Mizushina Y, Iida A, Ohta K, Sugawara F, Sakaguchi K.
Novel triterpenoids inhibit both DNA polymerase and
DNA topoisomerase. Biochem J 2000; 350 Pt 3: 757-763.
30 Viollet B, Horman S, Leclerc J, et al. Ampk inhibition in
health and disease. Crit Rev Biochem Mol Biol 2010; 45
(4): 276-295.
31 Hardie DG, Ross FA, Hawley SA. Amp-activated protein
kinase: a target for drugs both ancient and modern. Chem
Biol 2012; 19(10): 1222-1236.
32 Lee DH, Lee TH, Jung CH, Kim YH. Wogonin induces
apoptosis by activating the ampk and p53 signaling path-
ways in human glioblastoma cells. Cell Signal 2012; 24
(11): 2216-2225.
33 Yun SM, Jung JH, Jeong SJ, et al. Tanshinone iia induces
autophagic cell death via activation of ampk and erk and
inhibition of mtor and p70 s6k in kbm-5 leukemia cells.
Phytother Res 2014; 28(3): 458-464.
34 Russo GL. Ins and outs of dietary phytochemicals in can-
JTCM | www. journaltcm. com
cer chemoprevention. Biochem Pharmacol 2007; 74(4):
533-544.
35 Lee YK, Park SY, Kim YM, Lee WS, Park OJ. Amp kinase/
cyclooxygenase-2 pathway regulates proliferation and
apoptosis of cancer cells treated with quercetin. Exp Mol
Med 2009; 41(3): 201-207.
36 Park IJ, Yang WK, Nam SH, et al. Cryptotanshinone in-
duces g1 cell cycle arrest and autophagic cell death by acti-
vating the amp-activated protein kinase signal pathway in
hepg2 hepatoma. Apoptosis 2014; 19(4): 615-628.
37 Park JB, Lee MS, Cha EY, et al. Magnolol-induced apop-
tosis in hct-116 colon cancer cells is associated with the
amp-activated protein kinase signaling pathway. Biol
Pharm Bull 2012; 35(9): 1614-1620.
38 Wang WJ. Prevention and treatment of metabolic syn-
drome with integrated traditional chinese and Western
Medicine. Zhong Xi Yi Jie He Xue Bao 2004; 2(5):
390-395.
39 Yin J, Zhang H, Ye J. Traditional Chinese Medicine in
treatment of metabolic syndrome. Endocr Metab Immune
Disord Drug Targets 2008; 8(2): 99-111.
40 Yim NH, Kim A, Liang C, Cho WK, Ma JY. Guibitang, a
traditional herbal medicine, induces apoptotic death in
A431 cells by regulating the activities of mitogen-activated
protein kinases. BMC Complement Altern Med 2014; 14:
344.
41 Li WD, Hua BJ, Saud SM, et al, Colburn NH, Young
MR. Berberine regulates amp-activated protein kinase sig-
naling pathways and inhibits colon tumorigenesis in mice.
Mol Carcinog 2015; 54(10): 1096-1109.
42 Shen Y, Lu B, Zhang S, Ma ZJ. Diterpenoid c of radix cur-
cumae: an inhibitor of proliferation and inducer of apopto-
sis in human colon adenocarcinoma cells acting via inhibit-
ing mapk signaling pathway. Pharm Biol 2014; 52(9):
1158-1165.
43 Lin J, Chen Y, Wei L, et al. Ursolic acid inhibits colorectal
cancer angiogenesis through suppression of multiple signal-
ing pathways. Int J Oncol 2013; 43(5): 1666-1674.
44 Prasad S, Yadav VR, Sung B, et al. Ursolic acid inhibits
growth and metastasis of human colorectal cancer in an or-
thotopic nude mouse model by targeting multiple cell sig-
naling pathways: Chemosensitization with capecitabine.
Clin Cancer Res 2012; 18(18): 4942-4953.
45 Shakibaei M, Mobasheri A, Lueders C, et al. Curcumin
enhances the effect of chemotherapy against colorectal can-
cer cells by inhibition of nf-kappab and src protein kinase
signaling pathways. PloS one 2013; 8(2): e57218.
46 Zhang L, Ji Q, Liu X, et al. Norcantharidin inhibits tu-
mor angiogenesis via blocking vegfr2/mek/erk signaling
pathways. Cancer Sci 2013; 104(5): 604-610.
47 Wei L, Lin J, Wu G, et al. Scutellaria barbata d. Don in-
duces g1/s arrest via modulation of p53 and akt pathways
in human colon carcinoma cells. Oncol Rep 2013; 29(4):
1623-1628.
48 Law PC, Auyeung KK, Chan LY, Ko JK. Astragalus sapo-
nins downregulate vascular endothelial growth factor un-
der cobalt chloride-stimulated hypoxia in colon cancer
cells. BMC Complement Altern Med 2012; 12: 160.
49 Ponnurangam S, Mammen JM, Ramalingam S, et al. Ho-
nokiol in combination with radiation targets notch signal-
248 April 15, 2016 | Volume 36 | Issue 21 |
 Li WD et al. / Review
ing to inhibit colon cancer stem cells. Mol Cancer Ther
2012; 11(4): 963-972.
50 He BC, Gao JL, Luo X, et al. Ginsenoside rg3 inhibits
colorectal tumor growth through the down-regulation of
wnt/ss-catenin signaling. Int J Oncol 2011; 38(2):
437-445.
51 He BC, Gao JL, Zhang BQ, et al. Tetrandrine inhibits
wnt/beta-catenin signaling and suppresses tumor growth
of human colorectal cancer. Mol Pharmacol 2011; 79(2):
211-219.
52 Lau GK, Ye D. Stat3 implicated in the development of co-
lon cancer: a step closer for targeted therapy? Gastroenter-
ology 2010; 139(1): 353-355.
53 Morikawa T, Baba Y, Yamauchi M, et al. Stat3 expression,
molecular features, inflammation patterns, and prognosis
in a database of 724 colorectal cancers. Clin Cancer Res
2011; 17(6): 1452-1462.
54 Xie TX, Wei D, Liu M, et al. Stat3 activation regulates
the expression of matrix metalloproteinase-2 and tumor in-
vasion and metastasis. Oncogene 2004; 23(20):
3550-3560.
55 Yu H, Pardoll D, Jove R. Stats in cancer inflammation and
immunity: a leading role for stat3. Nat Rev Cancer 2009; 9
(11): 798-809.
56 Masciocchi D, Gelain A, Villa S, Meneghetti F, Barlocco
D. Signal transducer and activator of transcription 3
(stat3): a promising target for anticancer therapy. Future
Med Chem 2011; 3(5): 567-597.
57 Lin J, Chen Y, Cai Q, et al. Scutellaria barbata d don in-
hibits colorectal cancer growth via suppression of multiple
signaling pathways. Integr Cancer Ther 2013; 13(3):
240-248.
58 Zhang L, Zheng Y, Deng H, Liang L, Peng J. Aloperine
induces g2/m phase cell cycle arrest and apoptosis in
hct116 human colon cancer cells. Int J Mol Med 2014; 33
(6): 1613-1620.
59 Lin W, Zheng L, Zhuang Q, et al. Spica prunellae pro-
motes cancer cell apoptosis, inhibits cell proliferation and
tumor angiogenesis in a mouse model of colorectal cancer
via suppression of stat3 pathway. BMC Complement Al-
tern Med 2013; 13(1): 144.
60 Zhuang Q, Hong F, Shen A, et al. Pien tze huang inhibits
tumor cell proliferation and promotes apoptosis via sup-
pressing the stat3 pathway in a colorectal cancer mouse
model. Int J Oncol 2012; 40(5): 1569-1574.
61 Giles RH, van Es JH, Clevers H. Caught up in a wnt
storm: Wnt signaling in cancer. Biochim Biophys Acta
2003; 1653(1): 1-24.
62 Gehrke I, Gandhirajan RK, Kreuzer KA. Targeting the
wnt/beta-catenin/tcf/lef1 axis in solid and haematological
cancers: Multiplicity of therapeutic options. Eur J Cancer
2009; 45(16): 2759-2767.
63 Liu YZ, Wu K, Huang J, et al. The pten/pi3k/akt and wnt/
beta-catenin signaling pathways are involved in the inhibi-
tory effect of resveratrol on human colon cancer cell prolif-
eration. Int J Oncol 2014; 45(1): 104-112.
64 Saud SM, Young MR, Jones-Hall YL, et al. Chemopreven-
tive activity of plant flavonoid isorhamnetin in colorectal
JTCM | www. journaltcm. com
cancer is mediated by oncogenic src and beta-catenin. Can-
cer Res 2013; 73(17): 5473-5484.
65 Chien CC, Wu MS, Shen SC, et al. Activation of jnk con-
tributes to evodiamine-induced apoptosis and g2/m arrest
in human colorectal carcinoma cells: a structure-activity
study of evodiamine. PloS one 2014; 9(6): e99729.
66 Liu J, Shen M, Yue Z, et al. Triptolide inhibits colon-rec-
tal cancer cells proliferation by induction of g1 phase ar-
rest through upregulation of p21. Phytomedicine 2012; 19
(8-9): 756-762.
67 Murakami A, Ashida H, Terao J. Multitargeted cancer
prevention by quercetin. Cancer Lett 2008; 269(2):
315-325.
68 Hua H, Chen W, Shen L, Sheng Q, Teng L. Honokiol
augments the anti-cancer effects of oxaliplatin in colon
cancer cells. Acta Biochim Biophys Sin (Shanghai) 2013;
45(9): 773-779.
69 Itzkowitz SH, Yio X. Inflammation and cancer Ⅳ.
colorectal cancer in inflammatory bowel disease: The role
of inflammation. Am J Physiol Gastrointest Liver Physiol
2004; 287(1): G7-17.
70 Yao J, Zhao L, Zhao Q, et al. Nf-kappab and nrf2 signal-
ing pathways contribute to wogonin-mediated inhibition
of inflammation-associated colorectal carcinogenesis. Cell
Death Dis 2014; 5: e1283.
71 Kim DH, Hossain MA, Kang YJ, et al. Baicalein, an ac-
tive component of scutellaria baicalensis georgi, induces
apoptosis in human colon cancer cells and prevents aom/
dss-induced colon cancer in mice. Int J Oncol 2013; 43
(5): 1652-1658.
72 Wen XD, Wang CZ, Yu C, et al. Salvia miltiorrhiza (dan
shen) significantly ameliorates colon inflammation in dex-
tran sulfate sodium induced colitis. Am J Chin Med 2013;
41(5): 1097-1108.
73 Yang Y, Cai X, Yang J, et al. Chemoprevention of dietary
digitoflavone on colitis-associated colon tumorigenesis
through inducing nrf2 signaling pathway and inhibition
of inflammation. Mol Cancer 2014; 13: 48.
74 Shih CK, Chiang W, Kuo ML. Effects of adlay on azoxy-
methane-induced colon carcinogenesis in rats. Food Chem
Toxicol 2004; 42(8): 1339-1347.
75 Auyeung KK, Law PC, Ko JK. Combined therapeutic ef-
fects of vinblastine and astragalus saponins in human co-
lon cancer cells and tumor xenograft via inhibition of tu-
mor growth and proangiogenic factors. Nutr Cancer 2014;
66(4): 662-674.
76 Zhao X, Wang Q, Qian Y, Pang L. Cassia tora l.
(jue-ming-zi) has anticancer activity in tca8113 cells in vi-
tro and exerts anti-metastatic effects in vivo. Oncol Lett
2013; 5(3): 1036-1042.
77 Jia Y, Guan Q, Guo Y, Du C. Reduction of inflammatory
hyperplasia in the intestine in colon cancer-prone mice by
water-extract of cistanche deserticola. Phytother Res 2012;
26(6): 812-819.
78 Tang YJ, Yang JS, Lin CF,et al. Houttuynia cordata thunb
extract induces apoptosis through mitochondrial-depen-
dent pathway in ht-29 human colon adenocarcinoma
cells. Oncol Rep 2009; 22(5): 1051-1056.
249 April 15, 2016 | Volume 36 | Issue 21 |