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Cancer chemoprevention and therapy using chinese herbal medicine

Abstract

Traditional Chinese medicine (TCM) plays an indispensable role in cancer prevention and treatment. Chinese herbal medicine (CHM) is a key component of TCM and has been practiced for thousands of years. A number of naturally occurring products from Chinese herbs extracts exhibit strong inhibitory properties against carcinogenesis, including CHM single-herb extracts, CHM-derived active components, and CHM formulas (the polyherbal combinations), which regulate JAK/STAT, MAPK, and NF-ҡB pathways. The present review aims to report the cancer-preventive effect of CHM with evidence from cell-line, animal, epidemiological, and clinical experiments. We also present several issues that have yet to be resolved. In the future, cancer prevention by CHM will face unprecedented opportunities and challenges.

Background

It is estimated that approximately 14.1 million new cancer cases and 8.2 million cancer deaths occurred in 2012 worldwide [1]. Although many significant advancements in cancer treatment have been applied clinically, the morbidity and mortality of cancer remain high. An important reason for this unsatisfactory situation is that less attention has been paid to cancer prevention than treatment. Cancer can be caused by a variety of factors and may develop over a long time period, even during treatment. Medications that interrupt or reverse precancerous changes would be appealing and cost-effective in the battle against cancer.

The molecular prevention of cancer can be defined as the use of natural or synthetic agents that interrupt the prime drivers, key derangements, or the context in which these drivers act and derangements occur, before invasion across the basement membrane [2]. Chemoprevention is one aspect of the molecular prevention of cancer and was first defined by Sporn in 1976 [3]. Chemoprevention has been defined as the use of specific natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic development to a tumor, which involves natural drugs or micronutrients that inhibit cancer development either by blocking cancer initiation through DNA-damaging agents, or by arresting or reversing the progression of initiated cells, except for vaccines and therapeutic interventions against microbal related cancer by antimicrobial effects (e.g., Helicobacter pylori for gastric cancer) [4]. Plants and their effective ingredients account for a large proportion of natural agents that have been used for cancer prevention and treatment in traditional Chinese medicine (TCM) clinical practice for ages, and some naturally occurring products from Chinese herbal medicine (CHM) exert chemopreventive properties against carcinogenesis. Research regarding the anti-proliferative and cytotoxic effects of TCM is being pursued to develop evidence-based complementary and alternative medicine or drug discovery (Table 1), which indicates that TCM could be a potential approach for chemoprevention.

Table 1 Chinese Herbs in Chemoprevention Models

Preclinical Studies in Cancer Chemoprevention

In the initial search for chemopreventive agents, animal models have been used extensively in the efficacy testing of potential chemopreventive agents. CHM has shown efficacy against multiple types of cancer (Table 2). The chemopreventive effects of green tea intake have been shown in many in vivo studies. For the 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced skin papillomas, partial tumor regression or >90% inhibition of tumor growth, and marked inhibition of tumor growth (46–89%) were observed by intervention with green tea [5]. The incidences of esophageal mucosa lesions and esophageal tumors were significantly lower in the tea-treated rats (16–59% and 42–67%, respectively), compared with the control group (100% and 90%) [6]. Moreover, aqueous extract of green tea inhibited carcinogen-induced lung tumorigenesis in mice by 63% [7]. Polyphenon E exhibited a significant reduction in both tumor multiplicity (by 46%) and tumor load (by 94%) [8], while Epigallocatechin-3-gallate (EGCG) and Poly E-EGCG did not significantly inhibit lung tumor multiplicity [9].

Table 2 Mechanism of Action of Herbal Mixtures

As an extract of Prunella vulgaris L (PV) with 60% ethanol, P-60 could be used to treat B[a]P-induced lung cancer and decrease the tumor multiplicity by 90.3% [10]. Rosmarinic acid (RA) is a caffeic acid-related compound abundant in PV [11], whose oral administration completely prevented tumor formation induced by DMBA in hamsters [12] and had potent anti-cancer, anti-lipid peroxidative, and apoptotic effects on DMBA-induced skin carcinogenesis [13].

Honokiol, a plant lignan isolated from bark and seed of the cones of Magnolia officinalis, has shown chemopreventive effects on chemically induced skin cancer development [14]. It has been reported to delay the formation of papillomas with a 27–55% reduction in tumor multiplicity in mouse skin initiated by DMBA and promoted by TPA [15]. α-santalol combined with honokiol and magnolol as pretreatment decreased tumor multiplicity (up to 75%) on skin cancer in SKH-1 mice [16]. In an A549 lung cancer xenograft model, the combination of honokiol with cisplatin reduced the tumor volume (3.59-fold), compared with cisplatin alone [17]. Honokiol also reduced the percentage of bronchial disease exhibiing abnormal histology (squamous cell carcinoma, SCC) (from 24.4 to 11.0%, P = 0.01) and protected normal bronchial histology (20.5% in the control group and 38.5% in the honokiol-treated group, P = 0.004) [18].

Ginseng is another well-studied herb that shows strong chemopreventive activities. In a lung adenoma model induced by 48 weeks of DMBA, it decreased the average diameter of the largest lung adenomas by 23% and the incidence of diffuse pulmonary infiltration by 63%. In the Ginseng treatment group sacrificed 56 weeks after birth (aflatoxin B1 combined with Ginseng), the incidence of lung adenoma (29%) and hepatoma (75%) was decreased [19]. Oral administration of aqueous extract of red Ginseng decreased tumor multiplicity by 36% and the tumor load by 70% [8]. Korea White Ginseng (KWG) significantly reduced the percentage of SCC to 9.1%, compared with 26.5% in the control group. KWG also significantly reduced the squamous cell lung tumor area to an average of 1.5%, compared with 9.4% in the control group [20].

EFLA400 is a standardized Panax ginseng extract containing a high titre of ginsenoside Rg3 (>3.0% w/w). Oral administration of EFLA400 at pre-, peri-, and post-initiational phases showed reductions in tumor incidence (71.41 ± 6.73%, 72.19 ± 4.54%, and 70.46 ± 0.38% at 1, 3, and 10 mg/kg body weight, respectively), compared with 100% tumor incidence in the control group [21].

Scutellaria barbata D. Don (Lamiaceae) (SB) is known in CHM as Ban-Zhi-Lian. It has been used as an anti-inflammatory and anti-tumor agent. During an 18-week study, mice treated with DMBA plus TPA developed 3.5 tumors per mouse with a 34% tumor incidence on average. The application of 5, 10, 100, and 200 mg of SB extracts together with TPA reduced the numberof skin tumors by 35%, 43%, 50%, and 55%, respectively, and the percentage of mice with tumors were lowered by 45%, 55%, 60%, and 65%, respectively [22].

Curcumin (Diferuloylmethane) is the most important component of the spice turmeric and is derived from the rhizome of the East Indian plant Curcuma longa [23]. Curcumin in the diet of male F344 rats was shown to decrease the incidence of azoxymethane (AOM)-induced colon cancer, from 81% to 47% [24]. The combination of tea and curcumin significantly decreased the visible oral tumor incidence from 92.3% (24/26) to 69.2% (18/26) and the SCC incidence from 76.9% (20/26) to 42.3% (11/26). The combination also decreased the number of visible tumors and tumor volume by 52.4% and 69.8% and decreased the number of SCCs, dysplasic lesions, and papillomas by 62.0%, 37.5%, and 48.7%, respectively. Curcumin decreased the number of visible tumors (by 39.6%), the tumor volume (by 61.3%), and the number of SCCs (by 51.3%). Only the combination treatment decreased the proliferation index in SCCs [25]. Another study found that oral administration of curcumin during the initiation and postinitiation phases, as well as hesperidin at the initiation stage, caused a significant reduction in the incidence of tongue carcinoma (41–91% reduction, P < 0.05), and the order of chemopreventive efficacy was curcumin > β-carotene > hesperidin. The incidence of oral preneoplasia in rats fed with these compounds was also decreased (P < 0.05) [26].

Anti-tumor B (ATB), also called Zeng-Sheng-Ping, is a Chinese herbal mixture composed of six plants that has shown an anticancer effect in mouse models of bladder cancer [27], lung cancer [28, 29], and oral cancer [30]. Preclinical studies have shown that ATB could reduce the incidence of N-butyl-(4-hydroxybutyl) nitrosamide (BBN)-induced bladder cancer by 90.7% [27]. ATB caused a significant reduction in lung tumor multiplicity and tumor load (40% and 70%, respectively) [31]. In an oral SCC model, ATB decreased the incidence and multiplicity by 59.19% and 64.81%, respectively [30]. Both the ATB n-butanol fraction and water fraction significantly reduced the tumor volume by 32.6% (P < 0.01) and 22.9% (P < 0.01) in DMBA-induced buccal pouch carcinogenesis in hamsters [32]. Anti-tumor B inhibited 4-nitroquinoline-1-oxide (4NQO)-induced oral cancer development by 65% [30]. In a mouse model of 4NQO-induced oro-esophageal cancer, ATB (10% in diet) also significantly reduced the incidence of tongue SCC from 55.2% (16/29) to 22.2% (6/27) (P < 0.05) and slightly reduced the incidence of esophageal SCC from 34.5% (10/29) to 22.2% (6/27) [33]. In B[a]P-induced mouse lung adenomas, ATB reverted 40% of gene expression changes to normal levels [31], and most of these ATB-modulated genes were involved in cell proliferation. ATB is a potential agent for human lung adenocarcinoma carrying common genetic alterations.

Liu-Wei-Di-Huang-Wan (LP) is an ancient Chinese prescription consisted of six herbs: Rehmannia glutinosa, Cornus officinalis Sieb, Common Yam Rhizome, Alisma orientalis, Tree Peony Bark, and Poria cocos. It could inhibit the incidence of theurethan-induced lung pulmonary adenomas by 50–56% [34, 35]. To our knowledge, no relevant studies on LP in chemoprevention have been published in the last 20 years.

These results suggest that CHM could be a potential chemopreventive agent for cancer. Moreover, the findings from the in vivo studies have shown that CHM can exert potent chemopreventive effects against many types of cancer.

Mechanisms of Action

Considering the complicated factors of tumorigenesis, several pathways are believed to play an important role in chemoprevention. For example, the aberrant activation of intracellular signaling pathways confers malignant properties on cancer cells via the JAK/STAT and MAPK pathways [36, 37]. Chronic inflammation or tissue damage resulting in persistent inflammation promotes cell transformation through genetic damage or pro-inflammatory cytokines, thereby inducing chronic inflammation and tumorigenesis, which is activated by the NF-ҡB pathway [38]. Moreover, physiological cellular signaling mechanisms normally tightly regulate the ability of cells to gain access to and utilize nutrients, posing a fundamental barrier to transformation, which is abolished by the PI3K-Akt-mTOR pathway and then causes tumorigenesis [39].

Recent preclinical studies have improved our understanding of the mechanisms of CHM for chemoprevention (Table 2). In vitro studies, have demonstrated that green tea and EGCG could blocked carcinogenesis by affecting a wide range of signal transduction pathways: JAK/STAT [40], MAPK [41], PI3K/AKT [42], Wnt [43], NF-ҡB [44], Notch [45], and STAT3 [46]. The results demonstrated the beneficial effects of quercetin and EGCG on the suppression of the JAK/STAT cascade of CCA cells [40]. One study suggested that EGCG could suppress the proliferation anhe d induce tapoptosis of PANC-1 cells. Moreover, EGCG could upregulate PTEN expression and downregulate the expression of pAKT and p-mTOR to modulate the PI3K/AKT/mTOR signaling pathway [42]. EGCG exerts its cancer-preventive or anticancer activity against colon cancer cells by promoting the phosphorylation and proteasomal degradation of β-catenin through a mechanism independent of GSK-3βand PP2A [43]. The EGCG-induced apoptosis of HCCLM6 cells has been associated with a significant decrease in Bcl-2 and NF-kappaB expression. In addition, the expression of Bax, P53, caspase-9, and caspase-3 were increased, and Cytochrome C was released. These results suggest that EGCG inhibits the progression of cancer through cytocidal activity, and it is a potential therapeutic compound for hepatocellular carcinoma (HCC) [44]. EGCG has also been found to inhibit colorectal cancer by inhibiting HES1 and Notch2 [45]. Evidence shows that Polyphenon E(Poly E) treatment inhibits migration of MDA-MB231 breast cancer and human dermal microvascular endothelial (HMVEC) cells as well as the expression of VEGF and MMP9 through STAT3 [46]. Recent observations that β-catenin is upregulated in skin tumors suggests the possibility that the anti-skin carcinogenic effects of EGCG are mediated, at least in part, through its effects on β-catenin signaling. It was found that the EGCG treatment on the A431 and SCC13 human skin cancer cell lines resulted in reduced cell viability and increased cell death, and these cytotoxic effects were associated with the inactivation of β-catenin signaling [47]. EGCG inhibited the proliferation of Eca-109 and Te-1 cells in a time- and dose-dependent manner. Tumor cells were arrested in the G1 phase, and apoptosis was induced by ROS production and caspase-3 cleavage [48].

Prunella vulgaris (PV) extract and Rosmarinic acid (RA) also significantly eliminated ROS production and diminished IL-6 release to prevent UVB-caused DNA damage and oxidative stress to HaCaT keratinocytes [49]. RA inhibited TNF-α-induced ROS generation and NF-ҡB activation and enhanced TNF-α-induced apoptosis [50]. RA also suppressed the expression of MMP-9 by inhibiting NF-ҡB via the ERK1/2 signaling pathway as well as MMP-9 activity [51]. In addition, PV induced gene expression and the production of macrophage-related cytokines, such as TNF-α, IL-1b, and IL-6. PV stimulated macrophage activation via NF-ҡB transactivation and Mitogen-activated protein (MAP) kinase activation [52].

Multiple mechanisms have been implicated in the chemopreventive action of ginsenosides. One study showed that KWG functions as a chemopreventive agent through pathways involving AP-1, and KWG may partially depend on AP-1 for its chemopreventive function, possibly through the inhibition of JNK phosphorylation [20]. Ginsenoside Rg3, one of the major ingredients of heat-processed Ginseng, has been reported to inhibit the growth of various cancer cells. Rg3 induced apoptosis in MDA-MB-231 cells by blocking the NF-ҡB signaling pathway via the inactivation of ERK and Akt as well as the destabilization of mutant P53 [53].

BZL101, as an aqueous extract from SB, exhibits selective cytotoxicity through strong induction of ROS in tumor cells, leading to the hyperactivation of poly (ADP-ribose) polymerase, followed by a sustained decrease in the levels of NAD and the depletion of ATP [54]. Anti-tumor and anti-angiogenic activities of SB extracts in LoVo and human umbilical vein endothelial cells are partially mediated by the inhibition of Akt/protein kinase B. This inhibition was Akt kinase-specific, as it had no effect on PI3K, the upstream kinase of Akt, whereas the levels of phosphorylated Bad and FHKR, the two downstream targets of Akt, changed as the levels of Akt changed [55].

Curcumin has also been shown to exert significant growth inhibitory effects on pre-cancerous and carcinoma cell lines, such as epithelial breast cell lines MCF-10A, MCF-7, BT-474, SK-BR-3-h, and MDA-MB-231 [56], and lung cancer cell lines, such as A549, PC-9, H1975, and H1650 [23]. A number of studies have suggested that curcumin has the potential to target cancer stem cells through the regulation of self-renewal pathways (Wnt/beta-catenin, Notch, sonic hedgehog) and specific microRNAs involved in the acquisition of the epithelial-mesenchymal transition [57]. A recent study also demonstrated that curcumin and its analogues (PGV-0 and PGV-1) enhance the doxorubicin cytotoxicity to MCF-7 cells by inhibiting HER2 activity and activating NF-ƙB [58]. Other recent findings incidate that curcumin may subvert the TGF-β signaling to an alternative adipogenic differentiation program in addition to the previously established interference with the osteomimetic properties, thus inhibiting the bone metastatic processes in a chemopreventive as well as therapeutic setting [59].

A number of findings have suggested that honokiol targets multiple signaling pathways, including NF-ҡB, STAT3, epidermal growth factor receptor (EGFR), and mammalian target of rapamycin (m-TOR), which play an important role in cancer initiation and progression [60]. A recent study showed that honokiol inhibited lung SCC cells’ proliferation, arrested cells at the G1–S cell-cycle checkpoint, and induced apoptosis. By interfering with mitochondrial respiration, honokiol changed the redox status in the mitochondria, triggered apoptosis, and finally led to the inhibition of lung SCC [18].

Previous findings showed that ATB modulated the expression of genes on multiple signaling pathways, such as the Notch and Ras-MAPK pathways [29]. The number of BrdU-labeled positive cells in the oral pre-cancerous tissues was significantly decreased after treatment with ATB butanol or water fractions, which inhibited oral tumor cell growth and reduced the expression of MAPK. In addition, ATB promoted tumor cell apoptosis by increasing Caspase-3 expression but decreasing Bcl-2 protein production [32]. Cell proliferation, silver stained nucleolar organizer region (AgNOR), and proliferating cell nuclear antigen (PCNA)-labeling index were also significantly suppressed by ATB treatment [33]. The expression of EGFR and phosphorylated EGFR (Tyr1173) was also down-regulated by ATB [30].

Pharmacokinetics Studies

Pharmacokinetic (PK) data are important for understanding the interactions between Chinese herbs and cancer prevention. Satisfactory PK information on Chinese herbs is not available due to the low quantity and quality of relevant studies. However, there have been some PK analyses of green tea [61], Ginseng [62], and curcumin [63]. In a PK model for curcumin, the area under the curve for 10 and 12 g doses was estimated (mean +/− SE) to be 35.33 +/− 3.78 and 26.57 +/− 2.97 mug/mL x h, respectively, and C(max) was 2.30 +/− 0.26 and 1.73 +/− 0.19 mug/ml. The T (max) and T (1/2) were estimated to be 3.29 +/− 0.43 and 6.77 +/− 0.83 h. The ratio of glucuronide to sulfate was 1.92:1. The curcumin conjugates were present as either glucuronide or sulfate or mixed conjugates [63].

Toxicity Studies

Safety is as important as efficiency for chemoprevention agents. Green tea and curcumin are appealing for their low or non-toxicity. No pathologic changes in the liver, lungs, kidneys, etc., were found by microscopic examination after the administration of liposomal honokiol or liposomal honokiol plus cis-Dichlorodiamineplatinum (DDP). No adverse consequences occurred in gross measures, such as weight loss, ruffling of fur, life span, behavior, or feeding [17]. No overt signs of the SB-induced toxicity were observed, as judged by visual inspection of skin, gross morphological examination of major organs, and changes in body weights [22].

Several studies have shown that CHM, e.g., ATB, may cause some degree of toxicity in animals and human beings. Experimental animal studies and epidemiological surveys have uncovered green tea polyphenols’ (GTPs) toxicity at high doses, presumably due to pro-oxidative properties. Recent studies have shown that unlike low and medium dosage, diets containing high doses (1%) of GTPs aggravated colitis and colon carcinogenesis, caused nephrotoxicity and hepatotoxicity in mice, and down-regulated expressions of anti-oxidant enzymes and molecular chaperones [64, 65]. In a phase I trial to find the maximum tolerated dose of GTE, the dose-limiting toxicities were tremors, cough, constipation, and headache, which were thought to be caused by caffeine in GTE [66]. Another phase II study showed that GTE was well tolerated, although higher doses (750 and 1000 mg/m2) increased insomnia/nervousness without grade 4 toxicity [67]. ATB was well tolerated in A/J mice with doses as high as 400 g/kg diet. By giving diets composed of AIN-76A with ATB at 800 g/kg diet, mice lost body weight (>20%) within the first 2 weeks. These results are consistent with the long history (>26 years) of its safety profile in clinical trials and useage as herbal supplements [29]. However, the oral administration of ATB tablets caused severe side effects, including hepatic damage [68, 69], diarrhea, nausea, and rash [70], which limited the long-term administration of ATB for humans.

Cancer Chemoprevention Clinical Trials with Chinese Herbs

Cancer chemoprevention clinical trials are vital for guiding the use of CHM in cancer prevention. Several clinical trials have shown benefits of CHM in cancer chemoprevention (Table 3).

Table 3 Clinical Trials in Chemoprevention with Chinese Herbs

The treatment group by using green tea showed a 37.9% response rate after 6 months on human oral precancerous mucosa lesions, compared with the control arm. There were differences in the number and total volume of AgNOR and the proliferating index of PCNA in oral mucosa cell nuclei between the treated group and the control group [71]. A phase I study showed that a dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 ml] of green tea three times daily) for at least 6 months is recommended for future studies [66]. A phase II study of GTE suggested that higher doses of GTE may improve short-term (12 weeks) oral premalignant lesions’ (OPLs) outcome [67]. Many epidemiologic studies have been conducted to investigate the association between tea consumption and cancer. One conducted on 396 head and neck cancer (HNC) cases and 413 controls indicated an inverse association between HNC risk and green tea consumption, which appeared to be modified by alcohol drinking status [72]. For patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia, studies showed that twice daily EGCG (2000 mg per dose) administration resulted in a 31% sustained reduction of ≥20% in the absolute lymphocyte count, and 69% of patients with palpable adenopathy experienced a ≥ 50% reduction in the sum of the products of all lymph node areas, which could be correlated with reductions in lymphadenopathy (correlation co-efficient, 0.44; P = 0.02) [73, 74]. Another phase II trial is ongoing to study how green tea extract works in preventing breast cancer compared to a placebo in 1084 cases of postmenopausal women by evaluating its effects on breast cancer biomarkers, including mammographic density, plasma insulin-like growth factor 1, IGF binding protein 3, and estrone (ClinicalTrials.gov Identifier: NCT00917735).

CHM is very effective in the chemoprevention of upper aerodigestive tract tumors. ATB has a long history of safe usage in thousands of patients for more than 30 years. One clinical study showed an approximately 50% reduction in the cancerization rate of marked esophageal dysplasia with ATB [70]. In this clinical trial, more than 2500 cases of marked esophageal dysplasia were randomly divided into an ATB group and a placebo control group [70]. After 3 or 5 years of treatment, the progression of esophageal dysplasia to esophageal cancer was inhibited remarkably by 52.2% and 47.3%, respectively [70]. After 9 years, the inhibition rate was 42.1% [75]. Previous studies have suggested ATB to be a promising chemopreventive agent in smokers with bronchial dysplasia (Steve Lam, Professor, British Columbia Cancer Agency, Vancouver, Canada. sclam@interchange.ubc.ca; personal communication). In a pilot study of ATB in smokers with bronchial dysplasia, 20 current and former smokers with a smoking history of approximately 30 pack-years and one or more sites of bronchial dysplasia identified by fluorescence bronchoscopy-directed bronchial biopsies were treated with ATB for 6 months. Using combined histopathology and nuclear morphometry as the primary end point, site-specific analysis showed a complete regression rate of 64% in the ATB group and 26% in the placebo group (P = 0.002). The corresponding progressive disease rates were 9% and 12% respectively. In a randomized clinical trial on 112 patients with oral leukoplakia, ATB (4 tablets, 3 times per day for 8–12 months) reduced the size of oral lesion in 67.8% (40/59) patients, whereas the placebo was effective in 17% (9/53) patients (P < 0.01) [33].

In a clinical trial on chronic atrophic gastritis patients, the administration of red ginseng extract powder for 3 years exerted significant preventive effects on the incidence of non–organ-specific human cancers in males [76]. The maximum dose of BZL101 (40 g/day) was safe, well tolerated, and showed promising anticancer activity in heavily pretreated population of women with metastatic breast cancer [77]. Curcumin is still lacking evidence of chemopreventive activity in humans. All 5 patients received more than 6 months of curcumin and quercetin, and the mean percent of decrease in the number and size of polyps from baseline was 60.4% (P < 0.05) and 50.9% (P < 0.05), respectively. Minimal adverse effects and no laboratory abnormalities were noted [78]. A phase II chemoprevention study of curcumin was conducted to examine the effect of oral curcumin on various putative biomarkers of colonic tumorigenesis in smokers and found that curcumin can decrease the aberrant crypt foci number [79].

Perspectives and Conclusions

Cancer prevention by Chinese herbs is supported by studies from animal, cell culture, epidemiological, and clinical trials. However, Cancer prevention by Chinese herbs still a long way from clinical translation. More efforts are required for CHM standardization to ensure reproducibility, and the compatibility of different active compounds should be clarified, especially for the Chinese compound formula. In addition, with a more in-depth understanding of cross-reactivities and unintended consequences between CHM and other treatment, we could make better use of CHM in chemoprevention and treatment. Meanwhile, the increasing use of Chinese herbs around the world requires more scientific evidence for their putative harmlessness. The art of herbal medicine is to dissect pharmacologically and therapeutically valuable herbal drugs from harmful and toxic ones, and to develop combinations of medicinal plants as safe and efficient herbal remedies [80]. At this moment, the best way to ascertain the mechanism of chemopreventive agents on a molecular level is by using relevant biomarkers. Molecular markers can help in effectively determining the biological activity in a chemopreventive setting [81]. One review found that although 51 studies with more than 1.6 million participants have been done on cancer prevention, there is still limited evidence that green tea could reduce the incidence of liver cancer. The evidence for esophageal, gastric, colon, rectum, and pancreatic cancer remains conflicting [82]. Therefore, high methodological quality for clinical research is the key for clinical research to ascertain the cancer-preventive effect of Chinese herbs for cancer chemoprevention. Further research is expected to be done on developing agents with lower toxicity and higher efficacy for specific biomarkers and pathways, and targeting these therapies to individuals with specific genetic signatures should help to increase the utility of CHM in chemoprevention and treatment.

Abbreviations

4NQO:

4-nitroquinoline-1-oxide

AgNOR:

Silver stained nucleolar organizer region

AOM:

Azoxymethane

AP-1:

Activator protein-1

ATB:

Anti-tumor B

BBN:

N-butyl-(4-hydroxybutyl) nitrosamide

CH:

Chinese herbs

CHM:

Chinese herbal medicine

DDP:

Cis-Dichlorodiamineplatinum

DMBA:

7,12-dimethylbenz(a)anthracene

EGCG:

Epigallocatechin-3-gallate

EGFR:

Epidermal growth factor receptor

ENNG:

N-ethyl-N'-nitro-N-nitrosoguanidin

GSK-3ß:

Glycogen synthase kinase-3ß

GTE:

Green tea extract

GTPs:

Green tea polyphenols

HCC:

Hepatocellular carcinoma

HMVEC:

Human dermal microvascular endothelial cell

HNC:

Head and neck cancer

JAK/STAT:

Janus kinase/ signal transducer and activator of transcription

KWG:

Korea white ginseng

LP:

Liu-wei-di-huang Wan

MAP:

Mitogen-activated protein

MAPK:

Mitogen-activated protein kinase

MMP9:

Matrix metalloproteinase 9

NDEA:

N-nitrosodiethylamine

NMBzA:

N-nitrosomethylbenzylamine

NNK:

4-(methylnitro -samino)-1-(3-pyridyl)-1-butanone

NTCU:

N-nitroso-trischloro-ethylurea

OPL:

Oral premalignant lesions

PCNA:

Proliferating cell nuclear antigen

PI3K/AKT:

Phosphatidylin-ositol3-kinase / protein kinase B

PK:

Pharmacokinetic

Poly E:

Polyphenon E

PP2A:

Phospho-protein phosphatease 2A

PTEN:

Phosphatase and tensin homolog deleted on chromosome ten

PV:

Prunella vulgaris

RA:

Rosmarinic acid

ROS:

Reactive oxygen species

SB:

Scutellaria barbata

SCC:

Squamous cell carcinoma

TCM:

Traditional chinese medicine

TNF-a:

Tumor necrosis factor-a

TPA:

12-O-tetradecanoyl phorbol-13-acetate

VEGF:

Vascular endothelial growth factor

References

  1. 1.

    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

  2. 2.

    Maresso KC, Tsai KY, Brown PH, Szabo E, Lippman S, Hawk ET. Molecular cancer prevention: current status and future directions. CA Cancer J Clin. 2015;65:345–83.

  3. 3.

    Sporn MB. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res. 1976;36:2699–702.

  4. 4.

    Ferguson LR. Prospects for cancer prevention. Mutat Res. 1999;428:329–38.

  5. 5.

    Wang ZY, Huang MT, Ho CT, Chang R, Ma W, Ferraro T, et al. Inhibitory effect of green tea on the growth of established skin papillomas in mice. Cancer Res. 1992;52:6657–65.

  6. 6.

    Han C, Xu Y. The effect of Chinese tea on occurrence of esophageal tumor induced by N-nitrosomethylbenzylamine in rats. Biomed Environ Sci. 1990;3:35–42.

  7. 7.

    Wang ZY, Hong JY, Huang MT, Reuhl KR, Conney AH, Yang CS. Inhibition of N-nitrosodiethylamine- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorigenesis in a/J mice by green tea and black tea. Cancer Res. 1992;52:1943–7.

  8. 8.

    Yan Y, Wang Y, Tan Q, Hara Y, Yun TK, Lubet RA, et al. Efficacy of polyphenon E, red ginseng, and rapamycin on benzo(a)pyrene-induced lung tumorigenesis in a/J mice. Neoplasia. 2006;8:52–8.

  9. 9.

    Zhang Q, Fu H, Pan J, He J, Ryota S, Hara Y, et al. Effect of dietary Polyphenon E and EGCG on lung tumorigenesis in a/J mice. Pharm Res. 2010;27:1066–71.

  10. 10.

    Feng L, Jia X, Zhu M, Chen Y, Shi F. Chemoprevention by Prunella Vulgaris L. extract of non-small cell lung cancer via promoting apoptosis and regulating the cell cycle. Asian Pac J Cancer Prev. 2010;11:1355–8.

  11. 11.

    Qiang Z, Ye Z, Hauck C, Murphy PA, McCoy JA, Widrlechner MP, et al. Permeability of rosmarinic acid in Prunella Vulgaris and ursolic acid in Salvia Officinalis extracts across Caco-2 cell monolayers. J Ethnopharmacol. 2011;137:1107–12.

  12. 12.

    Anusuya C, Manoharan S. Antitumor initiating potential of rosmarinic acid in 7, 12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis. J Environ Pathol Toxicol Oncol. 2011;30:199–211.

  13. 13.

    Sharmila R, Manoharan S. Anti-tumor activity of rosmarinic acid in 7, 12-dimethylbenz(a)anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. Indian J Exp Biol. 2012;50:187–94.

  14. 14.

    Chilampalli S, Zhang X, Fahmy H, Kaushik RS, Zeman D, Hildreth MB, et al. Chemopreventive effects of honokiol on UVB-induced skin cancer development. Anticancer Res. 2010;30:777–83.

  15. 15.

    Konoshima T, Kozuka M, Tokuda H, Nishino H, Iwashima A, Haruna M, et al. Studies on inhibitors of skin tumor promotion, IX. Neolignans from Magnolia Officinalis. J Nat Prod. 1991;54:816–22.

  16. 16.

    Chilampalli C, Zhang X, Kaushik RS, Young A, Zeman D, Hildreth MB, et al. Chemopreventive effects of combination of honokiol and magnolol with alpha-santalol on skin cancer developments. Drug Discov Ther. 2013;7:109–15.

  17. 17.

    Jiang QQ, Fan LY, Yang GL, Guo WH, Hou WL, Chen LJ, et al. Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model. BMC Cancer. 2008;8:242.

  18. 18.

    Pan J, Zhang Q, Liu Q, Komas SM, Kalyanaraman B, Lubet RA, et al. Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function. Cancer Prev Res (Phila). 2014;7:1149–59.

  19. 19.

    Yun TK, Yun YS, Han IW. Anticarcinogenic effect of long-term oral administration of red ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detect Prev. 1983;6:515–25.

  20. 20.

    Pan J, Zhang Q, Li K, Liu Q, Wang Y, You M. Chemoprevention of lung squamous cell carcinoma by ginseng. Cancer Prev Res (Phila). 2013;6:530–9.

  21. 21.

    Panwar M, Kumar M, Samarth R, Kumar A. Evaluation of chemopreventive action and antimutagenic effect of the standardized Panax Ginseng extract, EFLA400, in Swiss albino mice. Phytother Res. 2005;19:65–71.

  22. 22.

    Suh SJ, Yoon JW, Lee TK, Jin UH, Kim SL, Kim MS, et al. Chemoprevention of Scutellaria bardata on human cancer cells and tumorigenesis in skin cancer. Phytother Res. 2007;21:135–41.

  23. 23.

    Mehta HJ, Patel V, Sadikot RT. Curcumin and lung cancer-a review. Target Oncol. 2014;9:295.

  24. 24.

    Samaha HS, Kelloff GJ, Steele V, Rao CV, Reddy BS. Modulation of apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and promotion. Cancer Res. 1997;57:1301–5.

  25. 25.

    Li N, Chen X, Liao J, Yang G, Wang S, Josephson Y, et al. Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin. Carcinogenesis. 2002;23:1307–13.

  26. 26.

    Tanaka T, Makita H, Ohnishi M, Hirose Y, Wang A, Mori H, et al. Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis by dietary curcumin and hesperidin: comparison with the protective effect of beta-carotene. Cancer Res. 1994;54:4653–9.

  27. 27.

    Fan X. Inhibitory effect of antitumor-B and retinamide on precancerous lesions of the bladder in rats. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1993;15:71–3.

  28. 28.

    Wang Y, Zhang Z, Kastens E, Lubet RA, You M. Mice with alterations in both p53 and Ink4a/Arf display a striking increase in lung tumor multiplicity and progression: differential chemopreventive effect of budesonide in wild-type and mutant a/J mice. Cancer Res. 2003;63:4389–95.

  29. 29.

    Zhang Z, Wang Y, Yao R, Li J, Yan Y, La Regina M, et al. Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in mouse lung tumor models. Oncogene. 2004;23:3841–50.

  30. 30.

    Wang Y, Yao R, Gao S, Wen W, Du Y, Szabo E, et al. Chemopreventive effect of a mixture of Chinese herbs (antitumor B) on chemically induced oral carcinogenesis. Mol Carcinog. 2013;52:49–56.

  31. 31.

    Wang Y, Zhang Z, Garbow JR, Rowland DJ, Lubet RA, Sit D, et al. Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs. Cancer Prev Res (Phila). 2009;2:634–40.

  32. 32.

    Guan XB, Sun Z, Chen XX, HR W, Zhang XY. Inhibitory effects of Zengshengping fractions on DMBA-induced buccal pouch carcinogenesis in hamsters. Chin Med J. 2012;125:332–7.

  33. 33.

    Sun Z, Guan X, Li N, Liu X, Chen X. Chemoprevention of oral cancer in animal models, and effect on leukoplakias in human patients with ZengShengPing, a mixture of medicinal herbs. Oral Oncol. 2010;46:105–10.

  34. 34.

    Li H, Jin YH, Jiang TL. Effect of Liuwei dihuang decoction on the expressionp of 53 gene in lung adenomas induced mice. Chinese journal of experimental formulas of. Chinese Med. 1997;3:17–9.

  35. 35.

    Jiang TL, Li XM, Shen JH. The inhibition of Liuwei dihuang decoction for urethane induced lung adenomas. J Tradit Chin Med. 1980;72:40.

  36. 36.

    Thomas SJ, Snowden JA, Zeidler MP, Danson SJ. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 2015;113:365–71.

  37. 37.

    Masliah-Planchon J, Garinet S, Pasmant E. RAS-MAPK pathway epigenetic activation in cancer: miRNAs in action. Oncotarget. 2016;7:38892–907.

  38. 38.

    Wang S, Liu Z, Wang L, Zhang X. NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009;6:327–34.

  39. 39.

    Lien EC, Lyssiotis CA, Cantley LC. Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. Recent Results Cancer Res. 2016;207:39–72.

  40. 40.

    Senggunprai L, Kukongviriyapan V, Prawan A, Kukongviriyapan U. Quercetin and EGCG exhibit chemopreventive effects in cholangiocarcinoma cells via suppression of JAK/STAT signaling pathway. Phytother Res. 2014;28:841–8.

  41. 41.

    Gao Y, Li W, Jia L, Li B, Chen YC, Tu Y. Enhancement of (−)-epigallocatechin-3-gallate and theaflavin-3-3′-digallate induced apoptosis by ascorbic acid in human lung adenocarcinoma SPC-A-1 cells and esophageal carcinoma Eca-109 cells via MAPK pathways. Biochem Biophys Res Commun. 2013;438:370–4.

  42. 42.

    Liu S, Wang XJ, Liu Y, Cui YF. PI3K/AKT/mTOR signaling is involved in (−)-epigallocatechin-3-gallate-induced apoptosis of human pancreatic carcinoma cells. Am J Chin Med. 2013;41:629–42.

  43. 43.

    Oh S, Gwak J, Park S, Yang CS. Green tea polyphenol EGCG suppresses Wnt/beta-catenin signaling by promoting GSK-3beta- and PP2A-independent beta-catenin phosphorylation/degradation. Biofactors. 2014;40:586–95.

  44. 44.

    Zhang Y, Duan W, Owusu L, Wu D, Xin Y. Epigallocatechin-3-gallate induces the apoptosis of hepatocellular carcinoma LM6 cells but not noncancerous liver cells. Int J Mol Med. 2015;35:117–24.

  45. 45.

    Jin H, Gong W, Zhang C, Wang S. Epigallocatechin gallate inhibits the proliferation of colorectal cancer cells by regulating notch signaling. Onco Targets Ther. 2013;6:145–53.

  46. 46.

    Leong H, Mathur PS, Greene GL. Green tea catechins inhibit angiogenesis through suppression of STAT3 activation. Breast Cancer Res Treat. 2009;117:505–15.

  47. 47.

    Singh T, Katiyar SK. Green tea polyphenol, (−)-epigallocatechin-3-gallate, induces toxicity in human skin cancer cells by targeting beta-catenin signaling. Toxicol Appl Pharmacol. 2013;273:418–24.

  48. 48.

    Liu L, Hou L, Gu S, Zuo X, Meng D, Luo M, et al. Molecular mechanism of epigallocatechin-3-gallate in human esophageal squamous cell carcinoma in vitro and in vivo.Oncol Rep. 2015;33:297–303.

  49. 49.

    Vostalova J, Zdarilova A, Svobodova A. Prunella Vulgaris extract and rosmarinic acid prevent UVB-induced DNA damage and oxidative stress in HaCaT keratinocytes. Arch Dermatol Res. 2010;302:171–81.

  50. 50.

    Moon DO, Kim MO, Lee JD, Choi YH, Kim GY. Rosmarinic acid sensitizes cell death through suppression of TNF-alpha-induced NF-kappaB activation and ROS generation in human leukemia U937 cells. Cancer Lett. 2010;288:183–91.

  51. 51.

    Choi JH, Han EH, Hwang YP, Choi JM, Choi CY, Chung YC, et al. Suppression of PMA-induced tumor cell invasion and metastasis by aqueous extract isolated from Prunella Vulgaris via the inhibition of NF-kappaB-dependent MMP-9 expression. Food Chem Toxicol. 2010;48:564–71.

  52. 52.

    Han EH, Choi JH, Hwang YP, Park HJ, Choi CY, Chung YC, et al. Immunostimulatory activity of aqueous extract isolated from Prunella Vulgaris. Food Chem Toxicol. 2009;47:62–9.

  53. 53.

    Kim BM, Kim DH, Park JH, Surh YJ, Na HK. Ginsenoside Rg3 inhibits constitutive activation of NF-kappaB signaling in human breast cancer (MDA-MB-231) cells: ERK and Akt as potential upstream targets. J Cancer Prev. 2014;19:23–30.

  54. 54.

    Fong S, Shoemaker M, Cadaoas J, Lo A, Liao W, Tagliaferri M, et al. Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria Barbata, towards breast cancer cells. Cancer Biol Ther. 2008;7:577–86.

  55. 55.

    Zhao Z, Holle L, Song W, Wei Y, Wagner TE, Yu X. Antitumor and anti-angiogenic activities of Scutellaria Barbata extracts in vitro are partially mediated by inhibition of Akt/protein kinase B. Mol Med Rep. 2012;5:788–92.

  56. 56.

    Terlikowska K, Witkowska A, Terlikowski S. Curcumin in chemoprevention of breast cancer. Postepy Hig Med Dosw (Online). 2014;68:571–8.

  57. 57.

    Li Y, Zhang T. Targeting cancer stem cells by curcumin and clinical applications. Cancer Lett. 2014;346:197–205.

  58. 58.

    Meiyanto E, Putri DD, Susidarti RA, Murwanti R. Sardjiman, Fitriasari a, et al: Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation. Asian Pac J Cancer Prev. 2014;15:179–84.

  59. 59.

    Dorai T, Diouri J, O'Shea O, Doty SB. Curcumin inhibits prostate cancer bone metastasis by up-regulating bone Morphogenic Protein-7. J Cancer Ther. 2014;5:369–86.

  60. 60.

    Kumar A, Kumar Singh U, Chaudhary A. Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities. Future Med Chem. 2013;5:809–29.

  61. 61.

    Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003;9:3312–9.

  62. 62.

    Kim HK. Pharmacokinetics of ginsenoside Rb1 and its metabolite compound K after oral administration of Korean red ginseng extract. J Ginseng Res. 2013;37:451–6.

  63. 63.

    Vareed SK, Kakarala M, Ruffin MT, Crowell JA, Normolle DP, Djuric Z, et al. Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomark Prev. 2008;17:1411–7.

  64. 64.

    Murakami A. Dose-dependent functionality and toxicity of green tea polyphenols in experimental rodents. Arch Biochem Biophys. 2014;557:3–10.

  65. 65.

    Inoue H, Maeda-Yamamoto M, Nesumi A, Tanaka T, Murakami A. Low and medium but not high doses of green tea polyphenols ameliorated dextran sodium sulfate-induced hepatotoxicity and nephrotoxicity. Biosci Biotechnol Biochem. 2013;77:1223–8.

  66. 66.

    Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, Hong WK, et al. Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol. 2001;19:1830–8.

  67. 67.

    Tsao AS, Liu D, Martin J, Tang XM, Lee JJ, El-Naggar AK, et al. Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila). 2009;2:931–41.

  68. 68.

    Zhang JZ. Zengshengping tablets- induced hepatic damage.Adverse Drug Reactions Journal. 2007;9:215.

  69. 69.

    Liu XD, Wen W. Serious liver damage associated with the use of airpotato yam in 1 case. Chinese Journal of Integrated Traditional and Western on Liver Diseases.Medicine. 1999:9:20.

  70. 70.

    Lin P, Zhang J, Rong Z, Han R, Xu S, Gao R, et al. Studies on medicamentous inhibitory therapy for esophageal precancerous lesions--3- and 5-year inhibitory effects of antitumor-B, retinamide and riboflavin. Proc Chin Acad Med Sci Peking Union Med Coll. 1990;5:121–9.

  71. 71.

    Li N, Sun Z, Han C, Chen J. The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc Soc Exp Biol Med. 1999;220:218–24.

  72. 72.

    Huang CC, Lee WT, Tsai ST, CY O, Lo HI, Wong TY, et al. Tea consumption and risk of head and neck cancer. PLoS One. 2014;9:e96507.

  73. 73.

    Shanafelt TD, Call TG, Zent CS, LaPlant B, Bowen DA, Roos M, et al. Phase I trial of daily oral Polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia. J Clin Oncol. 2009;27:3808–14.

  74. 74.

    Shanafelt TD, Call TG, Zent CS, Leis JF, LaPlant B, Bowen DA, et al. Phase 2 trial of daily, oral Polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Cancer. 2013;119:363–70.

  75. 75.

    Ding ZW, Gao F, Lin PZ. Long term effect of treating patients with precancerous lesions of the esophagus. Chinese Journal of Oncology. 1999;21:275.

  76. 76.

    Yun TK, Zheng S, Choi SY, Cai SR, Lee YS, Liu XY, et al. Non-organ-specific preventive effect of long-term administration of Korean red ginseng extract on incidence of human cancers. J Med Food. 2010;13:489–94.

  77. 77.

    Perez AT, Arun B, Tripathy D, Tagliaferri MA, Shaw HS, Kimmick GG, et al. A phase 1B dose escalation trial of Scutellaria Barbata (BZL101) for patients with metastatic breast cancer. Breast Cancer Res Treat. 2010;120:111–8.

  78. 78.

    Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, Wexner SD, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006;4:1035–8.

  79. 79.

    Carroll RE, Benya RV, Turgeon DK, Vareed S, Neuman M, Rodriguez L, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). 2011;4:354–64.

  80. 80.

    Efferth T, Kaina B. Toxicities by herbal medicines with emphasis to traditional Chinese medicine. Curr Drug Metab. 2011;12:989–96.

  81. 81.

    Ramshankar V, Krishnamurthy A. Chemoprevention of oral cancer: green tea experience. J Nat Sci Biol Med. 2014;5:3–7.

  82. 82.

    Boehm K, Borrelli F, Ernst E, Habacher G, Hung SK, Milazzo S, et al. Green tea (Camellia Sinensis) for the prevention of cancer. The Cochrane database of systematic reviews. 2009;8:Cd005004.

  83. 83.

    Huang SF, Horng CT, Hsieh YS, Hsieh YH, Chu SC, Chen PN. Epicatechin-3-gallate reverses TGF-beta1-induced epithelial-to-mesenchymal transition and inhibits cell invasion and protease activities in human lung cancer cells. Food Chem Toxicol. 2016;94:1–10.

  84. 84.

    Pan MH, Chiou YF, Wang YJ, Wang YF, Ho CT, Ho CF, et al. Multistage carcinogenesis process as molecular targets in cancer chemoprevention by epicatechin-3-gallate. Food Funct. 2011;2:101.

  85. 85.

    Hong OY, Noh EM, Jang HY, Lee YR, Lee BK, Jung SH, et al. Epigallocatechin gallate inhibits the growth of MDA-MB-231 breast cancer cells via inactivation of the beta-catenin signaling pathway. Oncol Lett. 2017;14:441.

  86. 86.

    Granja A, Pinheiro M, Reis S. Epigallocatechin Gallate Nanodelivery systems for cancer therapy. Nutrients. 2016;8:307.

  87. 87.

    Kim JW, Amin AR, Shin DM. Chemoprevention of head and neck cancer with green tea polyphenols. Cancer Prev Res (Phila). 2010;3:900–9.

  88. 88.

    Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med. 1992;21:334–50.

  89. 89.

    Conney AH, Zhou S, Lee MJ, Xie JG, Yang CS, Lou YR, et al. Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice. Toxicol Appl Pharmacol. 2007;224:209–13.

  90. 90.

    Liao J, Yang GY, Park ES, Meng X, Sun Y, Jia D, et al. Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in a/J mice by oral administration of green tea. Nutr Cancer. 2004;48:44–53.

  91. 91.

    Narisawa T, Fukaura Y. A very low dose of green tea polyphenols in drinking water prevents N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats. Jpn J Cancer Res. 1993;84:1007–9.

  92. 92.

    Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:10350–5.

  93. 93.

    Kim SJ, Amankwah E, Connors S, Park HY, Rincon M, Cornnell H, et al. Safety and chemopreventive effect of Polyphenon E in preventing early and metastatic progression of prostate cancer in TRAMP mice. Cancer prevention research (Philadelphia, Pa). 2014;7:435–44.

  94. 94.

    Klaunig JE, Kamendulis LM. Mechanisms of cancer chemoprevention in hepatic carcinogenesis: modulation of focal lesion growth in mice. Toxicol Sci. 1999;52:101–6.

  95. 95.

    Fujita Y, Yamane T, Tanaka M, Kuwata K, Okuzumi J, Takahashi T, et al. Inhibitory effect of (−)-epigallocatechin gallate on carcinogenesis with N-ethyl-N'-nitro-N-nitrosoguanidine in mouse duodenum. Jpn J Cancer Res. 1989;80:503–5.

  96. 96.

    Huang SP, Ho TM, Yang CW, Chang YJ, Chen JF, Shaw NS, et al. Chemopreventive potential of Ethanolic extracts of Luobuma leaves (Apocynum venetum L.) in androgen insensitive prostate cancer. Nutrients. 2017;9:948.

  97. 97.

    Horikawa K, Mohri T, Tanaka Y, Tokiwa H. Moderate inhibition of mutagenicity and carcinogenicity of benzo[a]pyrene, 1,6-dinitropyrene and 3,9-dinitrofluoranthene by Chinese medicinal herbs. Mutagenesis. 1994;9:523–6.

  98. 98.

    Liu T, Ma H, Shi W, Duan J, Wang Y, Zhang C, et al. Inhibition of STAT3 signaling pathway by ursolic acid suppresses growth of hepatocellular carcinoma. Int J Oncol. 2017;51:555–62.

  99. 99.

    Kang KA, Piao MJ, Ryu YS, Hyun YJ, Park JE, Shilnikova K, et al. Luteolin induces apoptotic cell death via antioxidant activity in human colon cancer cells. Int J Oncol. 2017;51:1169–78.

  100. 100.

    Teng B, Jiang J, Zhao L, Gao J, Chen J, Liu Z, et al. Ginsenoside PPD's antitumor effect via down-regulation of mTOR revealed by super-resolution imaging. Molecules. 2017;22 https://doi.org/10.3390/molecules22030486.

  101. 101.

    Kim JH, Choi JS. Effect of ginsenoside Rh-2 via activation of caspase-3 and Bcl-2-insensitive pathway in ovarian cancer cells. Physiol Res. 2016;65:1031–7.

  102. 102.

    Yang J, Yuan D, Xing T, Su H, Zhang S, Wen J, et al. Ginsenoside Rh2 inhibiting HCT116 colon cancer cell proliferation through blocking PDZ-binding kinase/T-LAK cell-originated protein kinase. J Ginseng Res. 2016;40:400–8.

  103. 103.

    Mao Q, Zhang PH, Yang J, Xu JD, Kong M, Shen H, et al. iTRAQ-based proteomic analysis of Ginsenoside F2 on human gastric carcinoma cells SGC7901.Evid Based Complement Alternat Med. 2016;2016:2635483.

  104. 104.

    Deng S, Wong CKC, Lai HC, Wong AST. Ginsenoside-Rb1 targets chemotherapy-resistant ovarian cancer stem cells via simultaneous inhibition of Wnt/beta-catenin signaling and epithelial-to-mesenchymal transition. Oncotarget. 2017;8:25897–914.

  105. 105.

    Surh YJ, Na HK, Lee JY, Keum YS. Molecular mechanisms underlying anti-tumor promoting activities of heat-processed Panax Ginseng C.A. Meyer. J Korean Med Sci. 2001;16 Suppl:S38–41.

  106. 106.

    Sun P, Sun D, Wang X. Effects of Scutellaria Barbata polysaccharide on the proliferation, apoptosis and EMT of human colon cancer HT29 cells. Carbohydr Polym. 2017;167:90–6.

  107. 107.

    Yang N, Zhao Y, Wang Z, Liu Y, Zhang Y. Scutellarin suppresses growth and causes apoptosis of human colorectal cancer cells by regulating the p53 pathway. Mol Med Rep. 2017;15:929–35.

  108. 108.

    Marconett CN, Morgenstern TJ, San Roman AK, Sundar SN, Singhal AK, Firestone GL. BZL101, a phytochemical extract from the Scutellaria Barbata plant, disrupts proliferation of human breast and prostate cancer cells through distinct mechanisms dependent on the cancer cell phenotype. Cancer Biol Ther. 2010;10:397–405.

  109. 109.

    Balakrishnan S, Manoharan S, Alias LM, Nirmal MR. Effect of curcumin and ferulic acid on modulation of expression pattern of p53 and bcl-2 proteins in 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Indian journal of biochemistry & biophysics. 2010;47:7–12.

  110. 110.

    Hahm ER, Arlotti JA, Marynowski SW, Singh SV. Honokiol, a constituent of oriental medicinal herb magnolia officinalis, inhibits growth of PC-3 xenografts in vivo in association with apoptosis induction. Clin Cancer Res. 2008;14:1248–57.

  111. 111.

    Chilampalli C, Guillermo R, Zhang X, Kaushik RS, Young A, Zeman D, et al. Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action. BMC Cancer. 2011;11:456.

  112. 112.

    Liu W, Zhang B, Chen G, Wu W, Zhou L, Shi Y, et al. Targeting miR-21 with Sophocarpine inhibits tumor progression and reverses epithelial-Mesenchymal transition in head and neck cancer. Mol Ther. 2017;25:2129–39.

  113. 113.

    Jung KH, Zhang J, Zhou C, Shen H, Gagea M, Rodriguez-Aguayo C, et al. Differentiation therapy for hepatocellular carcinoma: multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis. Hepatology. 2016;63:864–79.

  114. 114.

    Moses MA, Henry EC, Ricke WA, Gasiewicz TA: The heat shock protein 90 inhibitor, (-)-epigallocatechin gallate, has anticancer activity in a novel human prostate cancer progression model. Cancer prevention research (Philadelphia, Pa). 2015;8:249–57.

  115. 115.

    Jung H, Sok DE, Kim Y, Min B, Lee J, Bae K. Potentiating effect of obacunone from Dictamnus dasycarpus on cytotoxicity of microtuble inhibitors, vincristine, vinblastine and taxol. Planta Med. 2000;66:74–6.

  116. 116.

    Jiang J, Wang X, Cheng K, Zhao W, Hua Y, Xu C, et al. Psoralen reverses the P-glycoprotein-mediated multidrug resistance in human breast cancer MCF-7/ADR cells. Mol Med Rep. 2016;13:4745–50.

  117. 117.

    Zhu P, Wu Y, Yang A, Fu X, Mao M, Liu Z. Catalpol suppressed proliferation, growth and invasion of CT26 colon cancer by inhibiting inflammation and tumor angiogenesis. Biomed Pharmacother. 2017;95:68–76.

  118. 118.

    Liu C, Wu F, Liu Y, Meng C. Catalpol suppresses proliferation and facilitates apoptosis of MCF-7 breast cancer cells through upregulating microRNA-146a and downregulating matrix metalloproteinase-16 expression. Mol Med Rep. 2015;12:7609–14.

  119. 119.

    Lin HR. Triterpenes from Alisma Orientalis act as androgen receptor agonists, progesterone receptor antagonists, and glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2014;24:3626–32.

  120. 120.

    Xu Y, Zhu JY, Lei ZM, Wan LJ, Zhu XW, Ye F, et al. Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3. J Physiol Biochem. 2017;73:157–65.

  121. 121.

    Zhang L, Tao L, Shi T, Zhang F, Sheng X, Cao Y, et al. Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-kappaB and STAT3 pathways. IUBMB Life. 2015;67:778–88.

  122. 122.

    Li Y, Gong L, Qi R, Sun Q, Xia X, He H, et al. Paeoniflorin suppresses pancreatic cancer cell growth by upregulating HTRA3 expression. Drug Des Devel Ther. 2017;11:2481–91.

  123. 123.

    Wen H, Wu Z, Hu H, Wu Y, Yang G, Lu J, et al. The anti-tumor effect of pachymic acid on osteosarcoma cells by inducing PTEN and Caspase 3/7-dependent apoptosis. J Nat Med. 2017;

  124. 124.

    Ma J, Liu J, Lu C, Cai D. Pachymic acid induces apoptosis via activating ROS-dependent JNK and ER stress pathways in lung cancer cells. Cancer Cell Int. 2015;15:78.

  125. 125.

    Surh YJ, Na HK, Lee JY. Y.S K: molecular mechanisms underlying anti-tumor promoting activities of heat-processed Panax Ginseng C.A. Meyer. J Korean Med Sci. 2001;16:S38–41.

  126. 126.

    Surh YJ, Lee JY, Choi KJ. S.R K: effects of selected ginsenosides on phorbol ester-induced expression of cyclooxygenase-2 and activation of NF-kappaB and ERK1/2 in mouse skin. Ann N Y Acad Sci. 2002;973:396–401.

  127. 127.

    Feng L, Jia XB, Shi F, Chen Y. Identification of two polysaccharides from Prunella Vulgaris L. and evaluation on their anti-lung adenocarcinoma activity. Molecules. 2010;15:5093–103.

  128. 128.

    Collins NH, Lessey EC, DuSell CD, McDonnell DP, Fowler L, Palomino WA, et al. Characterization of antiestrogenic activity of the Chinese herb, prunella vulgaris, using in vitro and in vivo (mouse Xenograft) models. Biol Reprod. 2009;80:375–83.

  129. 129.

    Lamaison JL, Petitjean-Freytet C, Carnat A. Medicinal Lamiaceae with antioxidant properties, a potential source of rosmarinic acid. Pharm Acta Helv. 1991;66:185–8.

  130. 130.

    Rugo H, Shtivelman E, Perez A, Vogel C, Franco S, Tan Chiu E, et al. Phase I trial and antitumor effects of BZL101 for patients with advanced breast cancer. Breast Cancer Res Treat. 2007;105:17–28.

  131. 131.

    Walker JM, Maitra A, Walker J, Ehrnhoefer-Ressler MM, Inui T, Somoza V. Identification of Magnolia Officinalis L. bark extract as the most potent anti-inflammatory of four plant extracts. Am J Chin Med. 2013;41:531–44.

  132. 132.

    Tsai TH, Chou CJ, Chen CF. Disposition of magnolol after intravenous bolus and infusion in rabbits. Drug Metab Dispos. 1993;22:518–21.

  133. 133.

    Lee S, Khoo C, Halstead CW, Huynh T, Bensoussan A. Liquid chromatographic determination of honokiol and magnolol in hou po (Magnolia Officinalis) as the raw herb and dried aqueous extract. J AOAC Int. 2007;90:1210–8.

  134. 134.

    Ramadan G, Al-Kahtani MA, El-Sayed WM. Anti-inflammatory and anti-oxidant properties of Curcuma Longa (turmeric) versus Zingiber Officinale (ginger) rhizomes in rat adjuvant-induced arthritis. Inflammation. 2011;34:291–301.

  135. 135.

    Kaefer CM, Milner JA. The role of herbs and spices in cancer prevention. J Nutr Biochem. 2008;19:347–61.

  136. 136.

    Zhu K.J, Zhang Y.L, Ou,Yang. J.H, Liu YL, Lu LS, Zhang LZ, et al. Protect lung drinks prevention clinical epidemiological study of lung cancer. Hunan Journal of Traditional Chinese Medicine. 1997;(13):4–6.

  137. 137.

    K. J Z: The secondary prevention of traditional Chinese medicine of lung cancer. Journal of Hunan College of Traditional Chinese Medicine. 1997;4:2-3.

  138. 138.

    Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, Namkoong SE, et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev. 2003;12:383–90.

  139. 139.

    Wang J. Collaborative group for phase III clinical trial of Zeng Sheng-ping Phase III study. Results of phase III clinical trial of zeng sheng-ping in the treatment of patients with esophageal epithelial hyperplasia.Chinese Journal of Oncology. 2000;22:510–12.

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Funding

This study was sponsored by the Shanghai Municipality Science and Technology Commission Foundation Key Project (No.16401970700), the Shanghai Science and Technology Innovation Project of Traditional Chinese Medicine (No. ZYKC201601020), the Natural Science Foundation of China (No. 8170403581373623), and the Special Scientific Research for Traditional Chinese Medicine (No.201307006).

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All the data supporting the results are included in the article.

Author information

LJJ and LX conceived and designed the experiments. LJJ and LB performed the experiments and wrote the paper. YL, YBG, JS, and QW provide assistance with revising this manuscript. All authors read and approved the manuscript.

Correspondence to Ling Xu.

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Keywords

  • Cancer
  • Chemoprevention
  • Treatment
  • Chinese herbal medicine