Professional Documents
Culture Documents
1
Department of Traditional Chinese Medicine, Medical College of Jinan University; 2Department of Oncology,
Clifford Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong510632;
3
Clinical Institute, Jining Medical University, Jining, Shandong 272013; 4Department of Pancreatic Disease Center,
The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong510632, P.R. China
DOI: 10.3892/br.2015.537
antitumortargeted therapeutic agents. Worldwide, including releasing cytochromec and activating caspase3 proteins.
Western countries, TCM has been more accepted for its efficacy Additionally, it downregulated the expression of living and
in preventing and treating cancer. Investigations of targeted surviving genes and the Bax/Bcl2 ratio was unregulated.
therapy with herbal medicines will potentially provide future The study by Guoetal(20) demonstrated that oxymatrine
discoveries in oncological research. It is estimated that the effectively suppressed the cell proliferation and phosphoryla-
United States National Cancer Institute spends ~120million tion of EGFR (Tyr845), decreased phosphocofilin(Ser3) and
USD each year on TCMrelated research(5). While, based on phosphoLIMK1 (Thr508) without changing the total cofilin
the foundation of the system research of omics approach(6), and LIMK1 expression to inhibit the migration and invasion
the occurrence of cancer is known to be based on various of human gastric cancer cells. Huetal(21) studied the efficacy
factors, several phases, multigenes and complicated signaling of the TCM tubeimu on the MDAMB453 human breast
pathways(7,8). Cancer is considered a chronic health problem, cancer cell line. The study reported that the fragmentation of
similar to hypertension and diabetes by the World Health DNA could be observed by a fluorescence microscope at 72h
Organization, and therefore, the optimal effects of treatment and apoptosis frequently increased when the cells were in a
involve improving life quality, prolonging survival time and threedimensional compared to a twodimensional culture.
alleviating side effects. Therefore, the concept of survival with The research regarding the emodin azide methyl anthraqui-
cancer has been suggested(9). The following is the evidence none derivative(22) demonstrates that cytotoxic effects (such
reported in preclinical or clinical trials that demonstrates the as cell death) are through the arrest of the cell cycle and the
mechanism and efficacy of medicinal plants used as adjuvant induction of apoptosis in cancer cells. The overall molecular
treatment for cancer patients (also shown in TableI). mechanisms of emodin include cell cycle arrest and apoptosis,
promote the expression of hypoxiainducible factor1, gluta-
2. Inducing cellular apoptosis thione StransferaseP and Nacetyltransferase, and induce
glutathione phaseI andII detoxification enzymes to inhibit
Cell apoptosis is a form of programmed cell death that induces angiogenesis, invasion, migration and chemicalinduced
changes in cellular morphology and intracellular processes carcinogenDNA adduct formation. HER2/neu, CK2kinase
without inflammatory reactions. The procedures of apoptosis and p34cdc2 kinase were also inhibited in the human breast
are formed as follows: Receiving apoptotic signals leads to cancer cells.
cytomorphological alterations, the interaction between the
intermolecular apoptotic proteins, activation of the caspase 3. Reversing multidrug resistance
enzyme that acts upon cytoskeleton proteins, mitochondria,
nuclear membrane or chromatin to cleave proteins and Multidrug resistance (MDR) represents a prominent obstacle
substrates, causing the DNA to fragment, releasing the cyto- in cancer chemotherapy. Therefore, with the elucidation of
plasm enclosed by the plasma membrane, eventually leading the MDR mechanism, MDR has been associated with an
to cell death(1014). Currently, it is known that the extrinsic or adenosine triphosphate (ATP)dependent decrease in cellular
death receptor pathway, the intrinsic or mitochondrial pathway drug accumulation, which is attributed to the overexpression of
and the perforin/granzyme pathway are the major apoptotic certain ATPbinding cassette (ABC) transporter proteins(23).
pathways to activate caspases(12,1517). The apoptotic There are 9human MDR proteins that are generally members
process is involved in the maintenance of tissue homeostasis, of subfamilyC in the ABC superfamily(23). Although their
which can be triggered by a variety of stimuli, including cyto- structures are different, they share a similar ATPdriven trans-
kines, hormones, toxic insults and viruses. Once these stimuli port mechanism(24). However, due to their different locations,
seriously affect the selfhomeostasis of the cells, the genes, expression levels and activities, the drug resistance to chemo-
including oncogenes, tumorsuppressor genes, suicide genes therapy is varied. Using the method for identifying the MDR
and DNArepair genes, are activated and become cancerous mechanisms, there are three major mechanisms of drug resis-
resulting in the continuous division of the faulty cells. However, tance known in cells: i)Decreased watersoluble drug absorption,
the herbal medicines have an important role in the prevention including folate antagonists and nucleoside analogues, which
and treatment of cancer and execute their multiple therapeutic require transporters to enter cells; ii)various changes in cells
effects by inhibiting canceractivating enzymes, stimulating a occur that affect the capacity of cytotoxic drugs to kill cells,
DNA repair mechanism and promoting production of protec- such as alterations in cell cycle, increased repair of DNA
tive enzymes, thus, showing anticancer effects. damage, reduced apoptosis and altered metabolism of drugs;
Linetal(18) investigated the cellular effects of the ethane and iii)increased energydependent efflux of hydrophobic drugs
extract of Hedyotis Diffusa Willd. (EEHDW) in the HT29 that can easily enter the cells by diffusion through the plasma
human colon carcinoma cell. The study reported that EEHDW membrane(25). Pglycoprotein (Pgp), which belongs to the
inhibited the growth of HT29 cells by inducing cell morpho- first identified member of the ABC transporter superfamily of
logical changes, which reduce the cell viability due to DNA membrane transport proteins(26), represents the most common
fragmentation and loss of plasma membrane asymmetry, and capability of resistance to hydrophobic anticancer drugs by
also the collapse of mitochondrial membranes, the activation of actively extruding the drugs from the cells, including vinblas-
caspase9 and caspase3 and the increase of the proapoptotic tine, daunorubicin and paclitaxel. Therefore, patients with MDR
Bax to antiapoptotic Bcl2 ratio. Oxymatrine(19) is an isolated tumor types often only have limited options, but can withstand
extract from the traditional Chinese herb Sephora flavescent significantly high doses(27). Thus, with the evidence that
Ait, and its anticancer effect was examined on human pancre- more new drugs are deriving from herbal medicines, quercetin,
atic cancer PANC1 cells. The results showed its efficacy by epigallocatechin gallate, curcumin, capsaicin and gingerol have
Table I. Chinese medicines commonly used in cancer treatment.
Efficacy according to
Active components Tumor name bio-molecular levels Preclinical or clinical evidence of anticancer activity
Extract of Hedyotis Diffuse Human colon carcinoma cell Induced cell apoptosis Induced cell morphological changes, reduced cell viability, caused DNA
Willd. fragmentation, loss of plasma membrane asymmetry, collapse of the mitochondrial
membrane, activated caspase-9 and caspase-3
Oxymatrine (extract from Human pancreatic cancer, Induced cell apoptosis, Inhibited cell viability, induced cell apoptosis, downregulated the survivin genes,
Sephora Flavescent Ait) (PANC-1 cell), human inhibited tumor metastasis upregulated the ratio of Bax/Bcl-2, released cytochrome c and activated caspase-3
gastric cancer cell proteins. Suppressed cell proliferation, decreased phosphorylation of EGFR (Tyr845),
Cofilin (Ser3) and LIMK1 (Thr508)
Tubeimu of TCM Human breast cancer cell Induced cell apoptosis Induced cell apoptosis and DNA fragmentation
(MDA-MB-453)
Paris saponin VII extracted MCF-7/ADR cells Reversed multidrug resistance, Suppressed cell viability, as well as triggered apoptosis and drug resistance of
from Trillium tschonoskii induced cell apoptosis MCF-7/ADR cells, increased the expression of TNFR1, TRAILR1/DR4, TRAIL
Maxim R2/DR5 and FADD, and activated PARP, caspase8 and caspase3. Reduced
Pglycoprotein (P-gp) expression
Emodin azide Human breast cancer cells Induced cell apoptosis, Arrested cell cycle, induced cell apoptosis, promoted hypoxiainducible factor-1,
methylanthraguinone inhibited angiogenesis, tumor glutathione-S-transferase P and N-acetyltransferase expression, induced glutathione
derivative metastasis, reduced toxicity phase I and II detoxification enzymes to inhibit angiogenesis, invasion, migration
and chemical-induced carcinogen-DNA adduct formation and inhibit the activity of
HER2/neu, CK2 kinase and p34cdc2 kinase
Capsaicin and gingerol KB-C2 cells Reversed multidrug resistance Enhanced P-gp to anti-drug efflux transporter and increased the cytotoxicity of
BIOMEDICAL REPORTS 4: 3-14, 2016
vinblastine
Germacrone (the main Human breast cancer cells Reversed multidrug resistance, Germacrane and ADR increased the cytotoxicity compared to ADR alone and
component of Rhizma (MCF-7/ADR) induced cell apoptosis promoted cell apoptosis, downregulated the expression of anti-apoptotic proteins,
Curcuma) p53 and Bax, inhibited the expression of P-gp by the inhibition of the multidrug
resistance 1 (MDR1) gene promoter
Five tanshinones (including SW620 AD300 colon Reversed multidrug resistance, Decreased the digoxin efflux ratio, enhanced the cytotoxicity of doxorubicin and
cryptotanshine and cancer cells enhanced efficacy irinotecan in P-gp overexpressing SW620 AD300 colon cancer cells via increasing
dihydrotanshine) isolated from the intracellular accumulation of the P-gp substrate anticancer drugs, downregulated
Salvia miltiorrhiza (danshen) P-gp mRNA and protein expression and inhibited P-gp ATPase activity
Quinolones, indoloquinazoline CEM/ADR5000 leukemia, Reversed multidrug resistance Alleviated the activity of P-gp modulators
alkaloids derived from Evodia porcine brain capillary
ruaecarpa endothelial cells
Total extract of Carthami MDR KB-V1 cells Reversed multidrug resistance Showed a function of drug resistance, enhanced their chemosensitivities
Flos and enhanced efficacy and produced a general synergism in the cytotoxic effect
5
6
Table I. Continued.
Efficacy according to
Active components Tumor name bio-molecular levels Preclinical or clinical evidence of anticancer activity
Ethanol extract of Colon cancer cells, CRC Induced cell apoptosis, Induced cell apoptosis, inhibited angiogenesis invivo, reduced tumor size without
Scutellaria barbata mouse xenograft model inhibited angiogenesis and affecting body weight, suppressed the expression of key mediators of the pathway
a signaling pathway in tumor tissues, inhibited the expression of the target gene of the SHH signaling
pathway, vascular endothelial growth A (VEGF-A)
Xiaotansanjie decoction GCSCS Inhibited angiogenesis and Regulated the expression of Notch-1, Hes1, VEGF and ki-67, inhibited the cell
tumor growth, induced cell viability invivo, inhibited the expression of i Notch-1 and Hes1 to inhibit tumor
apoptosis growth
Baicalin MDA-MB -231 cells Inhibited metastasis and a Inhibited cell migration and invasion, suppressed tumor growth and the pulmonary
signaling pathway metastasis via blocking the p38 mitogen-activated protein kinase (MAPK) activity
and activated the inhibitor of p38 MAPK to decrease the expression of matrix
metalloproteinase (MMP)-2, MMP-9, uPA and uPAR through the P38-MAPK
signaling pathway
Pien Tze Huang Mouse model of Inhibited tumor and Reduced the expression of angiogenic factors, including inducible nitric oxide
colorectal cancer angiogenesis, suppressed synthase (iNOS), endothelial NOS, VEGF-A, basic fibroblast growth factor (bFGF),
signaling pathways as well as their specific receptors, VEGFR2 and bFGFR, to inhibit tumor
angiogenesis via suppression of multiple signaling pathways, such as STAT3, AKT
and MAPKs
Ganoderic acid Breast cancer cells Induced cell apoptosis, Suppressed cell growth, tumor angiogenesis and invasion, stimulated Me (GA-Me)
inhibited tumor angiogenesis the production of tumor necrosis factor- (TNF-), downregulated the expression of
and metastasis to suppress a various nuclear factor-B (NF-B) regulated genes [C-myc, cyclinD, Bcl-2, MMP-9,
signaling pathway VEGF, interleukin (IL)-6 and IL-8] to modulate the NF-B signaling pathway
NIE et al: MODERN APPLICATION OF TCM IN ONCOLOGY
TPA and saikosaponin HepG2 cell Suppressed signaling pathway Induced the phosphorylation of ERK, JNK and c-jun by activating the downstream
to inhibit angiogenesis transcriptional factors of the MAPK cascade (ATF2, c-jun, jun-B and c-fos),
decreased the efficacy of P15(INK4b)/p16(INK4a) RNAs, c-fos RNA protein and
AP-1-related DNAbinding activity
Nobiletin Human gastric Inhibited angiogenesis by Inhibited FAK and Pi3K/Akt activation to downregulate the enzyme activities,
adenocarcinoma suppressing signaling pathways protein expression and messenger RNA levels of MMP-2 and MMP-9, Ras, C-Raf,
AGS cells, to inhibit tumor metastasis Rac-1, Cdc42 and RhoA, increased the protein level of RhodB, decreased the
phosphorylation and degradation of I and NF- to inhibit the cell adhesion and
invasion
Gegen Quinlian decoction Human renal carcinoma Inhibited angiogenesis and Suppressed the enzyme activity of MMP2 to inhibit the expansion and
cells metastasis neoangiogenesis of cancer
Table I. Continued.
Efficacy according to
Active components Tumor name bio-molecular levels Preclinical or clinical evidence of anticancer activity
Astragalus polysaccharides S180 sarcoma-bearing mice Enhanced immunomodulatory Increased the IFN-, FasL and GrB mRNA levels, improved the activity of intestinal
activities intraepithelial T cytotoxicity of T cells and TNF- and IFN- levels
Wogonin SGC-7901 and MFC cells Enhanced immunomodulatory Exerted cytotoxicity to induce apoptosis of cancer cells, direct or indirect with DC,
activities promoted the recruitment of DC, T and NK cells into tumor tissues to invert the
expression levels of VEGF, B7H1 and RAE-1, dephosphorylate STAT3 to inhibit
its activation on tyrosine 705 to decrease the expression of B7H1 and MHC classI
chain-related proteinA and enhance calreticulin on the cell membrane
Mistletoe lectin-55 Colon cancer cell and Enhanced immunomodulatory Enhanced Agspecific activation and proliferation of CD4+ and CD8+ T cells and
colon cancer-bearing activities increased the number of tumor Agspecific CD8+ T cells with increasing production
BALB/C mice of IFN-, increased activation of NK and T cells to delay colon cancer
development
Alocasia cucullata Mouse tumor models Enhanced immunomodulatory Enhanced the key cytokines invivo, such as IL-2, IFN- and TNF-. Invitro,
and mammalian cancer cells activities activated the differentiation of THP-1 into macrophage-like cells with specific
macrophage surface markers, such as CD11b and CD14, and increased the induction
of TNF- and IL-1
Ganoderma lucidum Cancer patients in a Enhanced immunomodulatory Increased the mean concentration of plasma IL-2, IL-6 and IFN- and decreased
(lucid ganoderma) clinical trial, in mouse activities, induced cell the levels of IL-1 and TNF- in clinical trials, increased CD56+ (NK cells) and
models invivo and apoptosis, antimetastasis and CD3+ (T lymphocyte), CD4+ (T helper cells) and CD8+ (T suppressor cells) invivo
in cells invitro antiangiogenesis and invitro, cell cycle arrest, induced cell apoptosis, antiinvasion, antimigration,
BIOMEDICAL REPORTS 4: 3-14, 2016
Table I. Continued.
Efficacy according to
Active components Tumor name bio-molecular levels Preclinical or clinical evidence of anticancer activity
Curcumin MCF-7 cells, animal cancer, Induced cell apoptosis, tumor Enhanced cell apoptosis, enhanced Bcl-2/Bax expression, improved the kidney
models, colorectal metastasis, enhanced efficacy, function of creatinine/blood urea nitrogen and glutamic oxalacetic
cancer cells (CRC) improved life quality transaminase/glutamic pyruvic transaminase in the serum of animal trials with
mitomycinC treatment, chemosensitized the activity of 5-FU-based chemotherapy
invitro, inhibited cell proliferation, metastasis and downregulated NF-B-regulated
gene activation
Scutellaria baicalensis and Lewis lung carcinoma (LLC) Enhanced immunity, reduced Invivo, investigated in chemotherapy with cachectic symptoms, this combination
Qing-Shu-Yi-Qi-Tang invivo and invitro toxicity increased the Th1/Th2 ratio and NK cytotoxicity and increased the monocyte
chemoattractant protein-1 symptoms. Invitro, decreased the expression levels of
NF-B and muscle RING finger protein-1, decreased tumor masses and losses of
carcass and/or gastrocnemius muscle
Chinese herbal medicine Advanced non-small cell Enhanced efficacy, reduced CHM combined with conventional chemotherapy reduced nausea and vomiting at
(CHM) (Radix Astragalus, lung cancer patients toxicity, improved life quality toxicity grades of III-IV, prevented the decline of hemoglobin and platelets in patients
Radix Adenophorae, under chemotherapy at toxicity grades of I-V, reduced chemotherapy toxicity,
Radix Ophiopogonis, prolonged survival time, enhanced immediate tumor response and improved the
Radix Glycyrrhizae Poria Karnofsky performance status in advanced nonsmall cell lung cancer patients
NIE et al: MODERN APPLICATION OF TCM IN ONCOLOGY
become promising candidates(28) as they overcome MDR intercellular pro and antiangiogenic signaling pathways. These
potency in antitumor treatment. They act as MDR inhibitors, pathways control the activity of blood vesselassociated cells,
MDR modulators, MDR reversal agents or chemosensitizers including endothelial cells (ECs) and pericytes(37), which is
to reverse the resistance against anticancer drug(2530). formed by the initiation of cell proliferation and migration
Therefore, increasing studies are focusing on exploiting MDR in response to angiogenic stimulators: Vascular endothelial
reversal compounds from medicinal plants, as they have low or growth factor (VEGF), fibroblast growth factor2(FGF2),
no side effects for use in cancer treatment(29), to bypass drug interleukin8 (IL8), placental growth factor (PlGF), trans-
resistance in treating cancer, and eventually medicinal herbs forming growth factor (TGF), plateletderived growth
may be applied in the future in cancer adjuvant therapy. factor (PDGF), nitric oxide (NO), ephrins, angiopoietins, endo-
Capsaicin(8) and gingerol(8) have been reported to thelins, integrins, cadherins, chemokines and Notch(3739).
exhibit inhibitory effects on human Pgp. They increased the The crosstalk among the overexpression of growth factors,
intracellular concentration of Pgp substrates by inhibiting this hypoxiainducible factor and the dysregulation of tyrosine
anticancer drug efflux transporter. MDR carcinoma KBC2 kinase receptors is controlled by the phosphoinositide3kinase
cells were more susceptible to the cytotoxicity of vinblastine, as (PI3K)/Akt/mTOR(40), Ras/Raf/ERK/mitogenactivated
compared with vinblastine alone, when simultaneously treated protein kinase(MAPK) and hypoxiainducible factor (HIF)
with 50M capsaicin or gingerol(31). Therefore, capsaicin and regulatory pathways(41,42). The complicated formation of
gingerol can partially reverse MDR in cells that express Pgp. angiogenesis has provided a platform for tumor metastasis.
Germacrone(32), the main component of Rhizma curcuma, was The tumor hypoxiainduced epithelialtomesenchymal
tested on MCF7/adriamycin(ADR) MDR human breast cancer transition (EMT) also increased the metastatic phenotype of
cells. The combination of germacrane and ADR increased the tumors(43). When oxygen and nutrients are supplied to the
cytotoxicity when compared with ADR alone, and promoted tumor cells, angiogenesis has an important role in the growth,
cell apoptosis in a dosedependent manner. The apoptotic effect invasion and metastasis for the tumor. Therefore, when the
was enhanced with ADR, as analyzed by downregulating the tumor microenvironment has been converted by angiogen-
expression of antiapoptotic proteins p53 and Bax. In addition, esis, antiangiogenesis becomes a challenge for antitumor
germacrone inhibited the expression of Pgp by inhibiting the treatment. Therefore, numerous studies have inhibited tumor
MDR1 gene promoter. Taoetal(33) investigated the reversal angiogenesis from four aspects(37,38,42): One is restraining
of Pgp in colon cancer cells by five tanshinones isolated the inhibitor of tumor angiogenesis degraded by the basilar
from Salvia miltiorrhiza (danshen), the result demonstrated membrane, and the second is inhibiting the inhibitor of tumor
that only cryptotanshinone and dihydrotanshinone decreased angiogenesis for increasing endotheliocytes. The third is
the digoxin efflux ratio in a dosedependent manner and they preventing the activation of the growth factor that is associ-
enhanced the cytotoxicity of doxorubicin and irinotecan in ated with tumor angiogenesis. The final aspect is inhibiting
Pgp overexpressing SW620 AD300 colon cancer cells by the signaling pathways associated with tumor angiogenesis.
increasing the intracellular accumulation of the Pgp substrate However, the efficacy is unilateral, which may be insufficient
anticancer drugs, which possibly downregulate the Pgp mRNA and possibly generate drug resistance(44). Therefore, these
and protein expression and inhibit Pgp ATPase activity. problems highlighted the necessity for the exploitation of novel
Paris saponin VII (27), a type of saponin extracted from anticancer agents. However, there is numerous evidence(41)
Trillium tschonoskii Maxim, dosedependently suppressed cell that has proved that plantderived medicinal compounds may,
viability, aswellas triggered apoptosis and drug resistance of in a number of cases, be at least as effective in blocking angio-
MCF7/ADR cells. Furthermore, it also increased the expres- genesis as the currently used synthetic drugs, which exhibit
sion of TNFR1, TRAILR1/DR4, TRAILR2/DR5 and FADD, only a fraction of the side effects. The following are examples
and activated PARP, caspase8 and caspase3. By contrast, the of the plantderived medicinal compounds.
Pgp expression and activity were reduced. Quinolones, indolo- The TCM Scutellaria barbata is commonly used
quinazoline alkaloids that are derived from the plant medicine in cancer treatment. The ethanol extract of Scutellaria
Evodia ruaecarpa, were tested on CEM/ADR5000 leukemia barbata(45) was able to induce apoptosis of the colon cancer
and porcine brain capillary endothelial cells. The results cells and inhibit angiogenesis in a chick embryo chorioal-
showed that the quinolones are moderate modulators of Pgp lantoxic membrane model. In a colorectal cancer cell (CRC)
activity(34,35). Additionally, the drug resistance index of the mouse xenograft model invivo, it could reduce tumor size
total extract of Carthami Flos(CF) in MDR KBV1 cells and without affecting the body weight and suppress the expres-
its synergistic effects with other chemotherapeutic agents were sion of key mediators of the Sonic hedgehog (SHH) pathway
studied. The results revealed that CF showed a drug resistance in tumor tissues. The expression of the important target gene
index, according to the classic isobologram equation. However, of the SHH signaling pathway, vascular endothelial growth
in combination with other chemotherapeutic agents, it enhanced factorA(VEGFA), was also inhibited, which has an impor-
their chemosensitivities and provided a general synergism of the tant role in stimulating tumor angiogenesis. The study of the
cytotoxic effect(36). xiaotansanjie decoction(46) in regulating the expression of
Notch1, Hes1, VEGF and Ki67 was measured by western
4. Comprehensive efficacy on angiogenesis, cellular signal- blotting and reverse transcriptionpolymerase chain reaction
ing pathway and metastasis and the cell viability was measured by the MTT assay. The
data revealed that cluster of differentiation (CD)44+ gastric
Angiogenesis is the formation of new blood vessels and is cancer stem cells (GCSCS) showed more cell proliferation
a complex and regulated process that involves a number of and VEGF secretion compared to CD44 cells in vitro,
10 NIE et al: MODERN APPLICATION OF TCM IN ONCOLOGY
whereas invivo, the CD44 + GCSCS had a high expression that activate CD8 Tcells, and subsequently CD8 Tcells are
of Notch1 and Hes1, which was positively associated with activated by direct antigen presentation, via MHC classI or via
tumor growth. The study by Wangetal(47) reported that CD4 Tcellmediated activation. The tumor cell is ultimately
baicalin not only dosedependently inhibited MDAMB231 destroyed by direct cellmediated cytotoxicity, aswell as an
cell migration and in vitro invasion, but also suppressed indirect antibody complementmediated cytotoxicity(53).
the growth of the tumor and the pulmonary metastasis via However, the majority of tumors have been demonstrated to
blocking p38 MAPK activity and activated the inhibitor of lose the expression of MHC molecules, resulting in the loss
p38 MAPK which decreased the expression of matrix metal- of presenting tumor antigens, thus evading Tcell recogni-
loproteinase2 (MMP2), MMP9, urokinase plasminogen tion(40,53). In addition, when the balance of the immune
activator (uPA) and uPA receptor through the p38MAPK checkpoint was destroyed, certain tumors upregulated
signaling pathway. Pien Tze Huang(48) was tested on a inhibitory molecules to evade the immune response(40).
mouse model of colorectal cancer and the treatment reduced Due to the strong heterogeneity of cancer, exploring novel
the expression of angiogenic factors, including inducible effective drug targets and therapeutic strategies to over-
NO synthase (NOS), endothelial NOS, VEGFA, basic FGF come the problem is required. TCM, with a long history
(bFGF), aswellas their specific receptors VEGFR2 and of treating various diseases through modulating the human
bFGFR, to inhibit the tumor angiogenesis via suppressing immune response, offers a potential to be a remedy of the
multiple signaling pathways, such as STAT3, AKT and new immunomodulating regimen for cancer treatment. They
MAPKs. In addition, based on the investigation of ganoderic exert broad immunostimulatory activities by recruiting and
acidMe(GAMe)(49), the growth, angiogenesis and invasion activating different types of immune cells, such as dendritic
of breast cancer cells were suppressed. By contrast, tumor cells (DC), natural killer (NK) Tcells, T cells, macrophage,
necrosis factor (TNF ) was stimulated. Furthermore, monocytes(5456) and adjusting the production of cytokines
GAMe downregulated the expression of various nuclear (IFN, IL2, IL6 and IFN)(54,57,58) to fight against the
factor B (NF B)regulated genes (Cmyc, cyclin D, BCL2, tumor cells.
MMP9, VEGF, IL6 and IL8) to modulate the NF B In the study of astragalus polysaccharides(59) conducted
signaling pathway. Saikosaponin(50) was investigated on the on S180 sarcomabearing mice, the IFN FasL and GrB
HepG2 cell line and the results revealed that phosphorylation mRNA levels were increased and the activity of intestinal
of ERK was significantly induced by TPA and saikosa- intraepithelial Tcells in vivo was also improved. The
ponin , whereas the phosphorylation of JNK was induced cytokine production and cytotoxicity of Tcells and the
only by TPA and the phosphorylation of P38 was not induced levels of TNF and IFN were all markedly improved
by either. This reaction was derived from the activation of following treatment. The study of wogonin(54) treatment
the downstream transcriptional factors of the MAPK cascade revealed that it exerted cytotoxicity, directly or indirectly
(ATF2, cjun, junB and cfos). However, the inhibitor could with DC, to induce apoptosis of cancer cells (SGC7901 and
decrease the efficacy of p15(INK4b)/p16(INK4a) RNAs, MFC cells). The treatment also promoted the recruitment of
cfos RNA protein and AP1related DNAbinding activity DC, Tand NK cells into tumor tissues to invert the expres-
by TPA and saikosapanin, and cjun phosphorylation was sion levels of vascular endothelial growth factor, B7H1,
only reduced by TPA. A study of nobiletin(51) treatment and RAE1 in tumor tissues. Additionally, the treatment
of human gastric adenocarcinoma AGS cells reported an also dephosphorylated STAT3 to inhibit its activation on
inhibition of the activation of focal adhesion kinase and tyrosine705 in tumor cells, which contributed to a decrease
PI3K/Akt, which are involved in the downregulation of the in the expression of B7H1 and MHC classI chainrelated
enzyme activities, and protein and messenger RNA levels of proteinA and the enhancement of calreticulin on the cell
MMP2, MMP9, Ras, cRaf, Rac1, Cdc42 and RhoA. The membrane. Notably, these data indicated that wogonin could
protein level of RhoB was progressively increased, whereas be used in collaboration with a DC vaccine or activated
treatment decreased the phosphorylation and degradation lymphocytes for tumor therapy. In addition, active chinese
of inhibitor of Ba(I Ba) and the nuclear response element mistletoe lectin55 was tested on colon cancer, and the
of NF B also exerted inhibitory effects on the cell adhe- results demonstrated that it enhanced antigen (Ag)specific
sion and invasion. The TCM Gegen Qinlian decoction(52) activation and proliferation of CD4 + and CD8+ Tcells and
significantly suppressed the enzyme activity of MMP2 in increased the number of tumor Agspecific CD8+ Tcells with
human renal carcinoma cells to inhibit the expansion and increasing production of IFN. Of note, the treatment with
neoangiogenesis of cancer. ACML55(58) also showed increased activation of innate
lymphocytes, such as NK and T cells. These immune
5. Regulating the immunomodulatory activities responses significantly delayed colon cancer development
in colon cancerbearing BALB/C mice. Alocasia cucullata
To an extent, tumors produce a number of tumor antigens, (AC)(57), a Chinese medicine, was investigated on mouse
which are the primary triggers of the immune response. They tumor models cultured in mammalian cells, and the results
are activated via a major histocompatibility complex(MHC) showed that its antitumor effect was closely associated
and the T cell response. In the process of immunosurveillance, with a strong induction of key cytokines invivo, such as
they trigger Tcell activation to recruit other immune effector IL2, IFN and TNF. AC activated the differentiation of
cells with the expression of costimulatory molecules and THP1, a human monocytic cell line, into macrophagelike
secretion of chemokines and cytokines to regulate different cells in vitro, accompanied with specific macrophage
aspects of the immune response, including Th1 CD4 Tcells surface markers, such as CD11b and CD14, and increased
BIOMEDICAL REPORTS 4: 3-14, 2016 11
the induction of TNF and IL1. All these data verified angiogenesis lung cancer mouse models. Spontaneously, LQ
the potential of AC to be an alternative immunomodu- had antiangiogenic activity and prolonged the survival of
lating herbal remedy for anticancer treatment. Ganoderma tumorbearing mice compared with DOX. LQ was efficacious
lucidum (lucid ganoderma)(60), a traditional Chinese herb, against primary and metastatic lung cancer without weight
has been used extensively in East Asia for one thousand loss and organ toxicity, whereas CTX and DOX had opposing
years. Compounds of the extraction of Ganoderma lucidum outcomes. Invitro, the study proved that LQ had the potential
mixed in PCSPES (61,62) were administered to cancer to induce cell death on cancer cell lines compared to normal
patients in a clinical trial, in mouse models invivo and in cell lines. With regards to a review of Chinese herbal medi-
cells invitro. In the prostate cancer patients, it improved the cines (CHMs)(67) (astragalus, turmeric, ginseng, Huachansu
immunostimulating response with an increased concentra- injection and Kanglaite injection), data revealed that they
tion of plasma IL2, IL6 and interferon, and it enhanced have significant advantages in suppressing tumor progression,
the natural killer cell activity and decreased the production increasing the sensitivity of chemo and ratiotherapeutics
of plasma IL1 and tumor necrosis factor. Simultaneously, accompanied by lessening the damage of the treatment and
in patients with advancedstage cancer in a clinical trial, enhancing the immune system function of the organism
the statistical results showed that following surgery, the from the preclinical and clinical studies. Additionally, they
patients undergoing oral administration of lucid ganoderma reduce cancerrelated fatigue and pain and the symptoms of
extract for 12 weeks exhibited a significantly increased cachexia, aswellas resistance to respiratory tract infections,
mean concentration of plasma IL2, IL6 and IFN , and alleviation of gastrointestinal side effects (diarrhea, nausea
significantly decreased levels of IL1 and TNF. There was and vomiting) and protection of the liver function. The expres-
also a significant increase of CD56+ (NKcells) and a small sion of survivin was also decreased. However, the expression
increase of CD3+ (Tlymphocyte), CD4+(Thelper cells) and of caspase9 increased in H22 cells. Furthermore, in the study
CD8+ (Tsuppressor cells) with unchanged CD4:CD8 Tcell of Zhouetal(68), mitomycinC (MMC) and curcumin syner-
ratios, which were induced by the lucid ganoderma extract gistically enhanced apoptosis in MCF7 cells by activating
as compared to the baseline levels(63). With regards to the the caspases and enhancing the expression of Bcl2/Bax.
invitro and invivo studies, the anticancer mechanism of Additionally, curcumin significantly improved the kidney
lucid ganoderma treatment against the growth of different function of creatinine/blood urea nitrogen and glutamic
cancer cells appeared to be mediated by cell cycle arrest, oxalacetic transaminase/glutamic pyruvic transaminase in the
apoptosis, antiinvasion, antimigration, immunomodulation serum of animals undergoing MMC treatment. Furthermore,
and antiangiogenesis(60). This evidence greatly supported the study by Shakibaeietal(69) demonstrated that curcumin
the anticancer potential of lucid ganoderma. chemosensitized the activity of 5FUbased chemotherapy on
CRC accompanied with inhibition of cell proliferation, metas-
6. Enhancing the efficacy, reducing toxicity and improving tasis and downregulation of NF Bregulated gene activation.
the quality of life for patients Scutellaria baicalensis(70) and QingShuYiQiTang(70)
were investigated on tumorbearing mice with cachectic
Over a few decades, systemic chemotherapy and radio- symptoms undergoing chemotherapy, and this combination
therapy have been the optimal treatment options for the increased the Th1/Th2 ratio and NK cytotoxicity, and the
tumor patients owing to the limitations and drawbacks(9) expression of monocyte chemoattractant protein1 was also
of surgery, including patients that are diagnosed too late increased, whilst the expression levels of NF B and muscle
to undergo surgery and a number of complications occur- RING finger protein1 were decreased. Evidently the tumor
ring following surgery. However, the major problem in masses and losses of carcass and/or gastrocnemius muscle were
cancer chemoradiotherapy is the prolonged toxicity of the significantly decreased. In addition, data from a metaanalysis
wellestablished chemical drugs or the radioactive rays that regarding CHM as an adjunctive therapy for advanced
resulted in numerous side effects and complications, including nonsmall cell lung cancer reported that CHM combined with
pain, diarrhea, nausea, vomiting, hair loss and hepatotoxicity. conventional chemotherapy markedly reduced the nausea and
Even in advanced stages, certain patients show a syndrome vomiting at toxicity grade ofIIIIV and prevented the decline
of cachexia(64), which leads to a poor quality of life. Thus, of hemoglobin and platelets in patients under chemotherapy
the complementary and alternative medicines have become at a toxicity grade ofIV(71). A systematic review suggested
a preference for patients. Consequently, there is certain that CHM, as an adjuvant therapy, can reduce chemotherapy
evidence in preclinical and clinical trials that has proved toxicity, prolong survival time, enhance immediate tumor
that TCM can enhance the efficacy and reduce toxicity with response and improve the Karnofsky performance status in
chemoradiotherapy and improve the quality of life and func- advanced nonsmall cell lung cancer patients. The review
tional status of patients. concluded that LiuJunZiTang, PHY906, coumarin and
The study by Zhangetal(65) compared the efficacy of the aescine were capable of improving the postoperation symp-
TCM herbal mixture LQ(66) (a mixture of Chinese medicinal toms, such as fatigue, pain, appetite, diarrhea, nausea, vomiting
herbs, comprising Sinapis alba, Atractylodes macrocephala, and lymphedema in clinical trials(9). Additionally, ginseng,
Coix lacrymajobi and Polyporus adusta) against lung cancer Huangqi, BanZhiLian, TJ48, Huachansu injection, Shenqi
in mouse models using doxorubicin (DOX) and cyclophos- fuzheng injection and Kanglaite injection in combination with
phamide(CTX). LQ inhibited the tumor size and weight chemo or radiotherapy were capable of enhancing the efficacy
measured directly, aswellas by fluorescentprotein imaging and diminishing the side effects and complications caused
in subcutaneous and orthotropic experimental metastasis and by chemo and radiotherapy, including gastrointestinal side
12 NIE et al: MODERN APPLICATION OF TCM IN ONCOLOGY
Figure 1. Association of the anticancer mode of action with TCM in the tumor microenvironment. TCM anticancer activity involves targeting various steps
(cell proliferation, angiogenesis, cell signaling pathways, invasion, metastasis and multidrug resistance) to inhibit tumor development, reduce the toxicity of
other therapies to tumors in the microenvironments, and accordingly, to improve the quality of life for patients. TCM, traditional Chinese medicine; MRP,mul-
tidrug resistance protein; VEGF, vascular endothelial growth factor; PDGF, plateletderived growth factor; Pgp, Pglycoprotein.
effects, liver function damage and even bone marrow suppres- of translational science and molecular biology, herbs and
sion. combination formulas have been reported to treat cancer as an
effective therapy in preclinical or clinical trials. The database
7. Conclusion and future perspectives regarding the pharmacological activities and mechanisms
of natural compounds revealed that tumors carried diverse
Cancer is a multifactorial and multistep disease that can driver gene mutations and crosstalked with different intra-
change the tumor microenvironment, leading to alterations cellular signals in the tumor microenvironment, leading to
in tumor metabolism. The circulation of energy regarding carcinogenesis(74). Therefore, it is imperative to explore the
glucose, lipid and amino acid metabolism and the formed mechanism of TCM at the molecular levels to clarify the role
metabolites(7) (such as lipids, amino acids, nucleotides, of more TCM in curing disease, and additionally, to make a
certain inflammatory cytokines and HIF) affected the cancer scientific foundation for internationalization of TCM. Based
cell proliferation, autophagy, survival and invasion/metastasis on the main principles of TCM regarding dialectic approaches,
and cellular signaling by blocking their required nutrients, individualization and patients with different syndromes
their associated pathways(72) and inhibiting the activity of the require treatment with different approaches. Therefore,
regulated immune cells(73). However, the above evidence has TCM with regards to treating different syndromes in various
proved that TCM has comprehensive advantages in treating individuals requires clarification. In recent years, there have
cancer with regards to these aspects, which also presented been numerous studies of the Chinese medicinal compound
a close association with each other(Fig.1). Therefore, it monomer in the field of medical science, however, there are
may be advantageous to identify and develop novel natural various components in the herbal medicines, and whether
compounds, active ingredients, single herbs and combination there is an interaction of the functional impacts between
formulas or prescriptions in TCM with its multitargets and themselves by one approach or several ways remains to be
multisignaling pathways on the tumor, without significant elucidated. Therefore, further validation of the biodiversity
toxicity compared to single utilization with other therapies. of the herbal medicines in preclinical or clinical trials, either
Even though the theory of TCM in treating cancer is in the alone or in combination with existing therapy, is required to
early stages, in recent years, with the enhanced knowledge benefit more patients with cancer.
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