Research progress of traditional Chinese medicine monomers in intervening colorectal cancer by regulating MAPK signaling pathway

Shuang Li,Chen-Chen Zhao,Chu-Yi Zhang,Jing-Xuan Li,Wang Gao

1Graduate School of Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China.2Department of Oncology,Second Affliated Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300250,China.3First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,National Clinical Research for Chinese Medicine Acupuncture and Moxibustion,Tianjin 300193,China.4Department of Gastroenterology,Second Affliated Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300250,China.

Abstract The incidence rate and mortality rate of colorectal cancer in China are increasing year by year.Finding effective therapeutic strategies and interventions,especially exploring“highly effective and low toxic”drugs to prevent“inflammation-cancer”transformation,treat primary tumors,prevent tumor metastasis and reduce the toxicity and increase efficiency of existing therapies has become a hot topic of domestic and foreign scholars.The advantage of traditional Chinese medicine in the treatment of colorectal cancer is to reduce the postoperative recurrence rate,improve patients’symptoms and the quality of life of“tumor survivors”and prolong the survival time.This paper summarizes the tumor treatment strategies and research prospects of traditional Chinese medicine targeting mitogen activated protein kinase by sorting out the mechanism of traditional Chinese medicine extracts or effective components intervening colorectal cancer by regulating mitogen activated protein kinase signal pathway in tumor cells in recent years.

Keywords:traditional Chinese medicine monomer;mitogen activated protein kinase;colorectal cancer;research progress

Background

The incidence rate of colorectal cancer(CRC)in China has leapt to the second place of malignant tumors and the fifth place of mortality[1].The formation of CRC mostly starts from colonic polyps.The mutation or inactivation of tumor suppressor gene Adenomatous polyposis coli in adenoma cancer sequence almost exists in 80%–85% of sporadic CRC,while traditional serrated adenomas and sessile serrated lesions are the serrated pathway of CRC[2,3].

The treatment methods of CRC mainly include surgery,chemotherapy,targeted therapy,immunotherapy and traditional Chinese medicine(TCM),etc.Surgery is the first choice for the treatment of early CRC,but because of its high invasion and metastasis rate,the 5-year survival rate is only about 50%[4,5].Chemotherapy based on 5-fluorouracil is often accompanied by adverse reactions and side effects such as gastrointestinal reaction,bone marrow suppression and cardiotoxicity and the sensitivity decreases with the progress of treatment[6].With the emergence of targeted drugs,the effectiveness of monoclonal antibodies against epidermal growth factor receptor such as cetuximab and panituzumab,antiangiogenic drugs against vascular endothelial growth factor(VEGF)such as bevacizumab and remiximab and broad-spectrum kinase inhibitor regofinib has been confirmed by basic experiments and clinical studies[7].In recent years,the position of immunotherapy in CRC treatment has been recognized.The first-line treatment of microsatellite instability-high/dmmr advanced CRC with programmed death-1(PD)-1 inhibitors such as pabolizumab has been written into the guidelines of the Chinese Society of Clinical Oncology as the highest level class I recommendation,while the reliability and efficacy of immune combined chemotherapy,immune combined targeted therapy and double immunotherapy need to be confirmed by the results of phase III research[8].

The role of TCM in the treatment of malignant tumors has gradually become prominent.TCM has been widely involved in the whole treatment of CRC.The effective components of TCM can destroy the living environment of cancer cells,promote apoptosis,improve the tumor immune microenvironment,remove pathogens through the autoimmune system and enhance the body's immunity.Studies have confirmed that a variety of TCM monomers can target CRC cells,which has broad development prospects[9].

Search strategy

We searched electronic literature databases including PubMed,Embase,the Cochrane Library,China National Knowledge Infrastructure,Chinese Scientific Journals Database(VIP)Database,Chinese Biomedical Literature Service System(SinoMed)and Wanfang Database.

The search keywords are:Traditional Chinese Medicine,Chung I Hsueh,Hsueh,Chung I,Traditional medicine,Chinese,Zhong Yi Xue,Chinese Traditional Medicine;Colorectal Neoplasm,Colorectal,Neoplasms,Colorectal Tumors,Colorectal Tumor,Colorectal Cancer,Colorectal Cancers,Colorectal Carcinoma,Colorectal,Carcinomas;Mitogen Activated Protein Kinase Kinases,mitogen activated protein kinase(MAPK)Kinase,Mitogen-Activated Protein Kinase,c-Jun NH2-terminal kinase(JNK)1,JNK2,p38 MAPK,p38,MAPK-Extracellular signal-regulated kinase(ERK)Kinase,MAPK-ERK Kinases.

Relationship between MAPK signal pathway and CRC

Cell signaling pathway is a communication process of cell activities mediated by downstream genes and proteins.The dispersion of signal transduction process leads to the disorder of cellular mechanism and the occurrence of cancer[10].A unique feature of the occurrence and development of CRC is the disorder of disordered molecular signaling pathways.The study of the functions and interactions of multiple signaling pathways is helpful to provide new targets for the treatment of CRC[11].

There are three different subtypes in the MAPK family,including ERK(ERK1,ERK2),JNK(JNK1,JNK2 and JNK3)and p38(p38α,p38β,p38γ and p38δ)[12].Including epidermal growth factor receptor,hippo,notch,insulin-like growth factor receptor 1,NF-κβ.Adenylate activated protein kinase,p53,PI3K/AKT,transforming growth factor-β,Wnt and MAPK,various mutations mediated by various signal pathways can participate in biological processes such as CRC cell proliferation,differentiation,metastasis,angiogenesis and apoptosis[13].Activation of ERK can promote LoVo derived exo and HCT116 of CRC cells,induce cell proliferation and inhibit apoptosis;Tam proposed that the inhibition of JNK is a promising method to inhibit the epithelial mesenchymal transformation process of CRC cancer cells and cancer stem cell maintenance;CRC is also a good example of the dual role of p38:the inhibition of p38 can stimulate or inhibit the growth of CRC[14–17].In addition,Martínez-Limón et al.found p38γ participates in RAS transformation in a non phosphorylated manner,which is different from p38α’s inhibition of tumor[18].The expression of p38γ is selectively induced in CRC cells containing mutant RAS,so RAS signal transduction is affected by subtype dependent mechanism.

The experimental datas from Tabibzadeh show that MAPK is the most obvious mutation pathway involved in KRAS gene mutation in CRC except Wnt,which is of great significance for clinical and experimental research on MAPK pathway involved in regulating the occurrence,development and apoptosis of CRC cells[19].

Relationship between traditional Chinese medicine and CRC

There is no relevant record on the name of CRC in TCM.According to the pathogenic characteristics and clinical symptoms,it is classified into the categories of“intestinal accumulation”,“enteromania”and“l(fā)ocked anus hemorrhoids”.It is said that inLingshu·shuizhang“what is rectal cancer?The cold air acts on the outside of the intestines and struggles with the Qi that protects the human body.The Qi cannot grow because it is suppressed by the cold evil and the cold evil stays in the body,so the evil Qi takes advantage of the opportunity and the polyps grow...”it is recorded inTaiping Shenghui Fang Volume 60“Wind,cold,heat and poison work together on the large intestine,so the large intestine becomes weak and blood in the stool often occurs,so it is called‘intestinal wind’”.According to the“Yi Deng Xu Yan–accumulated pulse syndrome”,such as flatulence,hernia,abdominal mass,women’s abdominal caking disease,fever,fullness of chest and abdomen,hyperactivity of bowel sounds,etc.,are all symptoms of this kind.The occurrence of CRC is mostly caused by the loss of the spleen’s transport function due to the feeling of external evil Qi or internal damage,resulting in the retention of damp heat,cold dampness and dampness in the intestines.The“turbidity”,“poison”and“blood stasis”are mutually cemented and integrated into one.The long-term stay leads to the patient and cancer,forming the basic pathogenesis of“deficiency of positive Qi,coexistence of poison and blood stasis”[20,21].

Professor Liu Shenlin’s method for the treatment of digestive tract tumors focuses on peace,harmony and obedience.He attaches importance to regulating and tonifying the spleen and stomach,nourishing qi and blood,coordinating the viscera and supporting healthy qi.Professor Liu created the“prescription for strengthening the spleen,nourishing Zheng and eliminating symptoms”with the Jianpi Zisheng pill in the biography of He’s asthenia and fatigue and the Xuexue pill in Shen’s Zunsheng book according to the syndrome.Sufficient experimental data and clinical observation confirmed its remarkable curative effect;Professor Xu Zhenye attaches great importance to the role of blood stasis in the pathogenesis of malignant tumors and advocates the method of promoting blood circulation and removing blood stasis and dredging blood vessels to eliminate blood stasis[22,23].The“Feiyanning formula”established can significantly improve and alleviate patients’symptoms,enhance immune function and prevent tumor recurrence and metastasis;Professor Zhou Zhongying believes that cancer toxin blocks,the lesion is surly,induces many pathological factors such as phlegm turbidity,blood stasis,dampness turbidity and heat toxin,and consumes Qi and injures Yin[24,25].Therefore,based on syndrome differentiation,he runs through the method of“attacking evil and strengthening health”.Zhou Zhongying’s overall medication for the treatment of CRC takes Sijunzi decoction for tonifying qi and strengthening spleen as the basic formula and adds and subtracts anti-cancer antidotes such asAgrimoniae,Coicis Semen,Herba Hedyotidis Diffusae,Herba EuphorbiaeandHerba Scutellariae Barbatae,with good results[26,27].

Based on the above literature research and our team’s research,it is found that the method of“clearing heat and detoxification,promoting blood circulation and removing blood stasis,supplementing qi and warming Yang”has a certain curative effect on CRC.Here,we summarize the pharmacological effects of extracts or effective components of drugs,for example,heat clearing and detoxifying drugs such asRabdosia rubescens,Melilotus officinalisandScutellaria baicalensis Georgi,blood activating and removing blood stasis drugs such asCroci Stigma,Curcuma longaand piscis vinea and Qi tonifying and warming Yang drugs such asGinsengRadix Et Rhizoma,EpimediiFolium andGanodermalucidum and the action mechanism of its monomer was discussed based on the molecular level.

The mechanism of traditional Chinese medicine monomer regulating MAPK signaling pathway in CRC

Oridonin(ORI)is a natural terpenoid compound inRabdosia rubescens,which has many pharmacological effects such as anticancer,antibacterial,neuroprotective and immune regulation[28].Wu et al.proved that ORI can increase the phosphorylation of p38 MAPK,p38 MAPK specific inhibitor can reduce the anti proliferation effect of ORI in HCT116 cells and inhibiting p38 MAPK can reverse the decrease of phosphatase and tensin homologue(PTEN)phosphorylation induced by ORI[29].The activation of p38 MAPK induced by ORI can reduce the phosphorylation of PTEN and enhance the exogenous expression of PTEN,so as to enhance the anticancer effect of ORI;Liu et al.found that the anticancer effect of ORI was localized by p38 MAPK,which triggered the p53 signal in SW620 cells[30].The use of specific antibodies against bone morphogenetic protein 7(BMP7)signal could eliminate the promoting effect of ORI on the activation of p38 MAPK and p53,indicating that BMP7 partially mediated the anticancer activity of ORI by successfully activating the phosphorylation of p38 MAPK in SW620 cells.

Luteolin(3,4,5,7-tetrahydroxyflavone)is a flavonoid with anti-inflammatory,antioxidant,anti allergic and anti-cancer effects in different plants.It can prevent carcinogenic stimulation by regulating different signaling pathways,reduce the expression of inducible nitric oxide synthase and cyclooxygenase-2 and inhibit the expression of matrix metalloproteinase(MMP)-2 and MMP-9[31].Poto?njak et al.demonstrated that luteolin also increased the expression of autophagy protein Beclin-1,autophagy associated protein 5 and microtubule associated protein 1A/1B light chain 3β-I/II(LC3B-I/II)[32].Cytotoxicity is consistent with the activation of ERK1/2 and transcription factor forkhead box O3a(FOXO3a).MAPK inhibitor PD0325901 inhibits ERK dependent FOXO3a phosphorylation,resulting in increased FOXO3a expression and apoptosis and inhibits autophagy,suggesting that luteolin has antitumor effect on SW620 cells through ERK/FOXO3a dependent mechanism.

Baicalein(5,6,7-trihydroxyflavone)is a kind of flavonoids isolated from the root ofScutellaria baicalensis Georgi,which has the pharmacological effects of anti cardiovascular disease,anti-bacterial,anti viral,anti neurodegenerative disease,inducing cancer cell apoptosis,blocking cell cycle,inhibiting angiogenesis,metastasis and inflammation[33,34].Su et al.showed that baicalein can significantly up regulate the expression of decidual protein induced by progesterone and growth arrest and DNA damage induction 45α(Gadd45α)and trigger the phosphorylation of MAPKs[35].Inhibiting JNK/p38 signal can reduce the expression of Gadd45α,suggesting that there is a positive feedback loop between Gadd45α and JNK/p38.While Hsu et al.found that the ability of baicalein E to inhibit cell migration was related to the decreased expression and activity of MMP-2 and MMP-9,the inhibition of p38α/β could significantly eliminate the effects of baicalein E on cell migration and MMP-2/-9 activity,which confirmed that baicalein E inhibited cell migration mainly through p38 MAPK pathway[36].

Apigenin is an edible flavonoid anticancer drug widely existing in a variety of plants.It can show cell growth arrest and apoptosis in different types of tumors by regulating a variety of signal pathways[37].Lin Si et al.found that apigenin can significantly inhibit the proliferation of CRC cell CL187 and reduce the formation of CL187 colony[38].Typical apoptosis characteristics such as nuclear pyknosis of CL187 can be observed under fluorescence microscope.Further experiments found that apigenin can significantly down regulate the expression of p-AKT and p-ERK1/2 and up regulate the expression of p-JNK and p-p38 MAPK,indicating that apigenin induced CL187 cell apoptosis is related to the regulation of the expression of MAPK signal pathway related proteins.Zhang et al.found that apigenin(25μM)combined chrysin(25μM)can significantly reduce the clone number,migration and invasion ability of CRC cells SW480 and HCT-116[39].p38 MAPK agonist anisomycin can significantly reverse the antitumor effect of apigenin and chrysin,suggesting that they can synergistically inhibit the growth and metastasis of CRC cells by down regulating the activity of p38 MAPK/AKT pathway.

Coicis Semenis a common TCM for both medicine and food.Clinically,Kanglaite injection withCoicis Semenoil as the main raw material has been widely used in the treatment of cancer[40].Kuo et al.found thatCoicis Semenhas the characteristics of anti initiation,promotion and progression,and can block multi-stage carcinogenesis[41].The chemopreventive function ofCoicis Semeninvolves removing electrophilic reagents and reactive oxygen species,anti mutation,enhancing Nrf2 mediated detoxification and antioxidation,changing carcinogen metabolism and enhancing anti-tumor immunity.Son et al.confirmed that the inhibitory effect of Coix bud extract(Clse)on ERK1/2 pathway of HCT116 cells was reversed after administration of ERK1/2 activator PMA,while p38 and JNK were not significantly affected[42].Clse can inhibit the migration,invasion and adhesion of colon cancer cells under hypoxia by inhibiting ERK1/2 signaling pathway.

Quercetin is widely found in TCMs such asAgrimoniaeHerba,Sophora japonica Linn and has a wide range of biological effects such as anti-oxidation,anti-cancer,anti-inflammatory,anti diabetes and antibacterial[43].Yang et al.found that quercetin selectively activated JNK pathway of mutant KRAS in CRC,while SP600125 inhibited JNK phosphorylation and blocked quercetin induced apoptosis[44].Similarly,the research of Trinh showed that SP600125 can effectively restore the inhibitory effect of quercetin,which activates MAPK signaling pathway in a time-dependent manner,while quercetin increases the expression level of epithelial cell marker E-cadherin and inhibits the expression level of mesenchymal cell marker wavy protein and N-cadherin in a dose-dependent manner,indicating that quercetin induces mesenchymal epithelial transformation through JNK signaling pathway,effectively inhibit the migration and invasion of CRC cells[45].

Gambogenic acid,an active compound isolated from Garcinia,is a resin secreted from Garcinia,which can induce the differentiation of tumor cells and inhibit proliferation[46,47].Qiu et al.found that when the concentration of gambogic acid was≥1.0 μg/ml,it can inhibit the expression of Gankyrin protein and arrest the cell mitosis in G2/M phase,so as to inhibit the DNA synthesis of HCT116 cells and effectively induce the apoptosis of CRC cells[48].Zhao et al.confirmed that gambogenic acid induces the production of reactive oxygen species(ROS),triggers endoplasmic reticulum stress and activates inositol requiring enzyme-1α(IRE1α)and JNK pathway,acts on ROS/IRE1α/JNK axis and triggers apoptosis of CRC cells mediated by Noxa protein of Bcl-2 family[49].

Crocetin is a carotenoid with antioxidant,anti-inflammatory and anti-tumor activities extracted fromCroci Stigma[50].The experimental results of Zhang showed that after treating CRC cell line DU-145 with crocetin,the expression of NF-κβ,VEGF,MMP-9 andinflammation related genes high mobility group box 1 interleukin IL-6 and interleukin-8 decreased significantly,which confirmed that crocetin could inhibit the growth of CRC cells and prevent the formation of ducts by inducing apoptosis[51].On this basis,Khajeh et al.found that crocetin can inhibit the migration and proliferation of HCT-116 in CRC cells by inhibiting the expression of VEGF and MMP-9[52].Further,compared with untreated control cells,crocetin significantly increased the phosphorylation level of p-p38 MAPK at 400,600 and 800 μM(P＜0.01),but had no significant effect on the expression of p-focal adhesion kinase,suggesting that crocetin plays an anticancer role on HCT-116 cells by inducing p38 MAPK pathway to inhibit angiogenesis.

Curcumin(CUR)is a polyphenol extracted from the rhizome ofCurcuma longawith antioxidant,anticancer and anti-inflammatory effects[53].CUR can regulate different signal pathways and molecular targets such as growth factors,enzymes,transcription factors,kinases and inflammatory cytokines[54,55].The experiment of Wang et al.further showed that the inhibition of proliferation and apoptosis induced by Curcumin(CUR)was accompanied by the inhibition of the expression of insulin-like factor-1 receptor,which increased the expression of Bax in LoVo cells,decreased the expression of camp response element binding protein 1 and Bcl-2 and induced LoVo cell apoptosis by activating p38 MAPK and its downstream signal pathway[56].CUR significantly increased the expression of p38 phosphorylation in a concentration and time-dependent manner and decreased the expression of camp response element binding protein in a dose-dependent manner,but had no effect on the total level of p38.It was proved that CUR inhibited the growth and induced apoptosis of Lovo cells through insulin-like factor-1 receptor/p38 MAPK signaling pathway.

Deguelin is a kind of tumor chemopreventive agent extracted from piscis vinea,gentian arbore orFructus Corni,which inhibits tumor cell proliferation and malignant transformation by targeting angiogenesis and lymphangiogenesis,inhibiting cathepsin Z/focal adhesion kinase and hedgehog signal pathway,regulating autophagy and other ways[57].Chen et al.found that deguelin had a dose-dependent and time-dependent effect on CRC cell proliferation[58].The phosphorylated form of p38 MAPK increased 24 hours after administration,while there was no significant change in ERK1/2 and JNK phosphorylated or NF-κβ p65,indicating that p38 MAPK weakened the inhibitory effect of deguelin on cell proliferation;the tumor size and weight were significantly inhibited in the xenograft mouse model treated with deguelin.Terminal deoxynucleotidyl transferase dUTP nick-end labeling method showed that the tumor cell apoptosis in the treatment group was significantly better than that in the control group,which confirmed that deguelin participated in the proliferation and apoptosis of CRC cells through the activation of p38 MAPK pathway.

Homoharringtonine is a plant alkaloid with antitumor effect extracted fromCephalotaxus fortunei Hook.f,which can be used to treat a variety of blood system diseases by preventing the initial elongation step of protein synthesis and other unique mechanisms[59].The high expression of the erythropoietin-producing hepatocellular carcinoma B4 enhances the migration ability of CRC cell line in vitro and promotes tumor growth and vascularization in vivo[60].After studying its mechanism,Shi et al.confirmed that homoharringtonine inhibited MAPK/ERK1/2 in the downstream pathway of the erythropoietin-producing hepatocellular carcinoma B4 receptor,which is abnormally highly expressed in LoVo cells of CRC patients,so as to regulate cell cycle related molecules and proteins such as Mcl-1,Bax,Bad and Caspase-3 in mitochondrial apoptosis pathway,induce cell apoptosis and cell cycle arrest in S phase,and accelerate LoVo apoptosis of CRC cells[61].

Ginsenoside is one of the main components ofGinsengRadix Et Rhizoma.Rh2 and Rg3 have clear anticancer effects such as inducing apoptosis,anti proliferation,anti metastasis and anti angiogenesis in more than 60 ginsenosides[62–64].Chang et al.found that total saponins of panaxGinsengcombined with JNK and p38 inhibitors was applied to HCT116 and SW620 cells pretreated with inhibitors and after intervention with RPMTG(250 μg/ml),it could reduce the expression levels of p-JNK,p-p38 and pro apoptotic protein Bax,increase the expression of anti apoptosis protein Bcl-2 and significantly reverse the inhibitory effect of RPMTG on cell viability[65].It is suggested that RPMTG induced apoptosis is related to the activation of JNK and p38 MAPK signaling pathway.Further studies confirmed that RPMTG inhibits cell proliferation by regulating the activation of mitochondrial related pathway and MAPK signaling pathway,resulting in the arrest of CRC cell cycle in G0/G1phase and S phase.

Icariin is an isoprene flavonol glycoside extracted fromEpimedii Folium,which has many pharmacological properties such as antioxidant,antitumor and estrogen-like activities,especially the anticancer effect of inhibiting tumor growth,invasion,migration and inducing cell cycle arrest[66–68].Kim et al.found that icariin(ICA)significantly induced the phosphorylation of ERK and p38 MAPK in HCT-116 cells[69].The results of further live/death experiments showed that tumor necrosis factor related apoptosis inducing ligand and ICA could induce 49% of HCT116 colon cancer cells to apoptosis.It was confirmed that ICA increased the expression of cell surface death receptors by producing ROS,activating ERK signaling pathway and inducing transcription factor C/EBP homologous protein,making cancer cells sensitive to tumor necrosis factor related apoptosis inducing ligand induced apoptosis.

Ganodermalucidum polysaccharide(GLP)consists of(1→3),(1→6)-α/β-composition of glucan,glycoprotein and water-soluble heteropolysaccharide[70].GLP has a wide range of biological activities and can play an anti-cancer role through a variety of mechanisms such as anti proliferation,promoting apoptosis,anti metastasis,anti angiogenesis and improving patients’immune function[71].Autophagy can inhibit tumor occurrence and development and promote tumor survival and proliferation in different cancers.MAPK/ERK is an important regulator of autophagy[72,73].Pan et al.found the MAPK/ERK inhibitor PD98059 of 20 μM can significantly down regulate the expression of Microtubule-associated protein LC3-II protein induced by GLP in cells,suggesting that the activation of MAPK/ERK is the reason for the initiation of autophagy induced by GLP;GLP inhibits tumor growth and autophagy flux in vivo,which indicates that GLP is an effective autophagy inhibitor and can interfere with autophagy lysosomal fusion[74].It is confirmed that CRC cell apoptosis can be achieved by activating MAPK/ERK mediated autophagy volume accumulation induced by GLP.

Thymoquinone(2-isopropyl-5-methyl-1,4-benzoquinone,TQ)is a bioactive component extracted from Semen nigrum essentiale oleum,which has many pharmacological effects such as anti-inflammatory,anti-tumor,analgesic and nerve protection[75].Flow cytometry,M30 cell death and Caspase-3/7 activation confirmed that TQ could inhibit the proliferation of human CRC cell DLD-1 through apoptosis,but had no cytotoxicity to normal human small intestinal FHs74Int cells.The activation of JNK and ERK in MAPK pathway by TQ is completely eliminated under the inhibition of strong antioxidant N-acetylcysteine.These two kinases have survival promoting activity under the intervention of specific ERK and JNK inhibitors PD98059 and SP600125 in TQ–induced apoptosis,which shows the relationship between the pro oxidative effect of TQ and its apoptotic effect in CRC,and proves the protective effect of MAPK[76,77].

Summary and Prospect

The advantage of TCM is that individual treatment can be carried out through the method of syndrome differentiation and treatment and the TCM with efficacy and performance in line with the patient’s constitution and syndrome performance can be selected.At present,some achievements have been made in the transformation and development of TCM monomers or empirical compounds such as xiaoaiping injection,Kanglaite injection,Brucea javanica oil emulsion and Cinobufacin injection,which also provides theoretical support and clinical treatment ideas for the treatment of CRC with TCM andprescription.

This paper aims to accurately grasp the mechanism and biological effects of TCM through the summary of molecular level experimental research on the action targets of TCM monomers,significantly improve the bioavailability of drugs and reduce toxicity and side effects and provide new ideas and new schemes for the clinical treatment of various diseases including CRC when combined with targeted drugs or chemotherapy drugs.See Table 1 for the summary of the regulatory effect of Chinese herbal monomer on MAPK signal pathway on CRC.

Table 1 Regulatory effect of TCM monomer on MAPK signaling pathway in colorectal cancer

There are also some problems worthy of further discussion in the treatment of CRC with TCM and its monomers,such as how to grasp the time and dose of TCM intervention in CRC treatment;the pathophysiological activities of tumor cells are affected by many factors except the complex interaction network between various signal mechanisms.How to choose single target and multi-target;how to weigh the advantages and disadvantages of TCM intervention for individuals with complex disease conditions and types;at present,most of the data come from experimental research at the molecular level and there is still a lack of convincing clinical control observation.How to promote the close combination of clinical and basic research;monomer is effective,compound is not necessarily equally effective,etc.These problems are the difficulties of TCM research under the quantitative mode of Western medicine.Nowadays,it can be clear that the process of TCM modernization is a process of continuous research and deepening from simplicity to complexity,from part to whole.