Advances in Pharmacological Research on Active Components of Traditional Chinese Medicine in the Treatment of Inflammatory Bowel Disease-related Bowel Cancer

Weijie PENG, Qing LUO, Weibo DAI

Zhongshan Hospital of Traditional Chinese Medicine, Affiliated to Guangzhou University of Chinese Medicine, Zhongshan 528401, China

Abstract In recent years, with the modern development of traditional medicine, the research on the treatment of inflammatory bowel disease and bowel cancer is increasingly deep. This paper reviews the pharmacological research progress of flavonoids, alkaloids, polyphenols, polysaccharides, steroids and saponins in the treatment of inflammatory bowel disease and canceration.

Key words Inflammatory bowel disease, Inflammation-related bowel cancer, Traditional Chinese medicine, Active constituent

1 Introduction

Inflammatory bowel disease (IBD) is a kind of chronic gastrointestinal inflammation, and has become a global digestive system disease, and its incidence is higher and higher in America, Europe, Asia and other places[1]. The gastrointestinal structure and function of IBD patients are damaged for a long time, and the typical clinical symptoms include weight loss, diarrhea, hematochezia,etc.The probability of conversion from enteritis to colorectal cancer will significantly increase in these patients[2]. Colorectal cancer (CRC) is the third most common cancer in the world. There are millions of new cases and deaths in the world every year. The average incidence rate of CRC in the general population is 61.8/100 000, while the probability of CRC in IBD patients is 165.4/100 000, which increases nearly 3 times. Colorectal cancer is the main cause of death in IBD patients, accounting for 10%-15% of all-cause mortality in IBD[3-4]. Its pathogenesis is not clear, similar to other cancer, and related to environmental factors, gene mutations, immune disorders, epigenetic modification,etc.There is a close relationship between inflammation and cancer, and the deterioration of inflammatory environment will promote the occurrence of tumor. Therefore, without active treatment, patients with inflammatory bowel disease are very likely to develop from inflammation to atypical hyperplasia over time, and finally canceration[5]. In recent years, traditional Chinese medicine has received extensive attention in the treatment of enteritis and its canceration, in which the monomer components of it have played an important role, and its mechanism has been studied gradually. This paper reviews the pharmacological research of flavonoids, alkaloids, polyphenols, polysaccharides, steroids and saponins in the treatment of inflammatory bowel disease and cancer transformation.

2 Pharmacological progress of active components of traditional Chinese medicine in the treatment of inflammatory bowel disease and canceration

2.1 FlavonoidsSilybin is a kind of flavonoid lignans, which has many effects including anti-inflammation, anti-oxidation, scavenging oxygen free radicals, anti-cancer,etc.Zheng Rongjuanetal.proved that silybin can pass through the IL-6/STAT3 pathway. The number of colonic tumor in silybin treatment group was significantly less than that in AOM/DSS group, especially the difference in tumor diameter≥4 mm between the two groups was significant. Therefore, silybin had obvious therapeutic effect on inflammation-related bowel cancer induced by AOM/DSS[6].

Haixia Zhaoetal.found that by AOM/DSS modeling, the incidence, diversity and tumor size of colorectal cancer decreased by 60%, 55.4% and 42.6%, respectively, after intragastric administration of isoglycyrrhizin (ISL) for 12 weeks. In addition, ISL inhibited the polarization of M2 macrophages. This change was accompanied by the decrease of pge2 and IL-6 signals. Importantly, clearance of macrophages with chlorophosphonic acid (Clod) or zoledronic acid (ZA) reversed the effect of ISL. At the same time,invitrostudies also showed that ISL limited M2 polarization of RAW264.7 cells and mouse peritoneal macrophages, and inactivated pge2/PPARδ and IL-6/STAT3 signaling pathways. On the contrary, exogenous addition of pge2 or IL-6, or overexpression of constitutive activated STAT3 reversed ISLS-mediated polarization inhibition of M2 macrophages[7].

Yang Yetal.studied the effect and mechanism of diflavone on inflammation-related bowel cancer and found that it was a new type of activator of Nrf2 pathway and had a protective effect on cell damage induced by oxidative stress. Trace concentration of digitalis flavonoids (10 μM) increased the expression of Nrf2, nuclear translocation and the expression of downstream II antioxidant enzymes. In addition, digitalis flavonoids reduced H2O2-induced oxidative stress and cell death through p38 MAPK-Nrf2/ARE pathway.Invivo, 50 mg/kg digitalis flavonoids significantly reduced the incidence, number and size of tumor induced by AOM-DSS[8].

Wu Xianetal.found that NOB had a significant effect on AOM/DSS-induced colitis associated cancer, which could significantly reduce the level of iNOS in colonic tissue of AOM/DSS-treated mice, up-regulate Nrf2-dependent enzymes, and significantly regulate key signal proteins, thus reducing cell cycle progression. Intake of NOB led to the presence of NOB and its metabolites in colon tissue, and inhibited the occurrence of colonitis-related colorectal cancer by down-regulating iNOS, inducing antioxidant enzymes and blocking cell cycle progression[9].

Liu Lijieetal.studied tanshinone IIA, an active constituent inSalviamiltiorrhiza, and showed that it significantly reduced the formation of tumor in mice treated with AOM/DSS. Compared with model mice, tanshinone IIA also reduced intestinal permeability, thus reducing neutrophil infiltration in colonic mucosa and intestinal inflammation in mice. In mechanism, tanshinone IIA down-regulated NF-κB signal pathway in AOM/DSS-treated mouse colonic tumor.Invitroexperiments further confirmed that tanshinone IIA inhibited LPS-induced neutrophil activation[10].

Emodin is an anthraquinone derivative. Zhang Yunshaetal.used the AOM/DSS model of colonitis-related intestinal tumor to describe the effects of emodin on inflammation and tumor at the 3rd, 5thand 14thweek after the onset of AOM. At all three time points, emodin decreased the recruitment of inflammatory cells[CD11b(+) and F4/80(+)], the expression of cytokines (TNFα, IL1α/β, IL6, CCL2, CXCL5) and proinflammatory enzymes (COX-2, NOS2) in tumor microenvironment, and promoted the recruitment of CD3(+)T lymphocytes at the 14thweek. Emodin reduced the incidence of precancerous lesions (adenomas) of cancer at the 3rdweek, dysplasia and cancer at the 5thweek, and the incidence, size and invasiveness of cancer at the 14thweek. Emodin also relieved acute clinical intestinal symptoms (i.e., bleeding and diarrhea) during drinking DSS[11].

Zhu Xiaohui evaluated the chemotherapeutic effect of dihydromyricetin (DMY) on irinotecan (CPT-11) or gemcitabine (GM) in AOM/DSS-induced colonitis-related colorectal cancer model and Min (Apc-Min/+) mouse model. The data showed that DMY could promote the CPT-11 effect in both AOM/DSS and Apc-Min/+ cancer mouse models, but had no impact on the GM effect. In AOM/DSS cancer, tumor was sensitive to 100 mg/kg DMY at 100 or 200 mg/kg CPT-11. DMY-driven CPT-11 chemotherapy induced an increase in the level of IgG and a decrease in the abundance of Clostridium. In Min model, the combination of CPT-11 and 20 mg/kg DMY could prevent the formation of tumor, but it didn’t work when combining with 100 mg/kg DMY[12].

Naringin is a kind of flavonoids. Zhang Yushengetal.found that oral administration of naringin could prevent AOM/DSS-induced ulcerative colonitis and canceration, and there were no obvious side effects. Naringin alleviated the severity of colonitis and colorectal adenomas by inhibiting myeloid-derived suppressor cells (MDSCs), pro-inflammatory mediators GM-CSF/M-CSF, IL-6, TNF-α and NF-κB/IL-6/STAT3 cascade in colonitis and colorectal adenomas. Naringin-treated mice showed normal colorectal tissue structure. Electron microscopic analysis showed that autophagy induced by strong endoplasmic reticulum (ER) stress was inhibited. Naringin inhibited the secretion of ER transmembrane proteins in colorectal mucosal cells, such as GRP78 ATF6, IRE1α and activated PERK phosphorylated eIF-2α and autophagosome complexes ATG3, ATG5, ATG7, ATG12, ATG16 and ATG16L1[13].

2.2 AlkaloidsPiperlongumine (PL) piperamide is an alkaloid with anti-inflammatory, antibacterial, anti-angiogenic, antioxidant, anti-tumor and anti-diabetes activity. PL can down-regulate the expression of pro-inflammatory cytokines cyclooxygenase-2 and interleukin-6 and epithelial-mesenchymal transformation-related factors β-catenin and snail, inhibit the inflammation of mouse colonitis induced by DSS, reduce the number of large tumors (diameter>2 mm) of mouse colorectal cancer induced by AOM/DSS, but can not improve the symptoms of colonitis, reduce the incidence of colon tumor and the number of small tumors (diameter<2 mm)[14]. Zhou Yishanetal.established inflammation-related bowel cancer model in Balb/c mice by AOM/DSS and administered neferine, and found that it could effectively regulate the protein expression of RIP3, COX-2, iNOS, NF-κB p65, p-p65, β-catenin, STAT3 and p-STAT3, and reduce the volume and quantity of tumor, thus achieving the therapeutic effect[15].

It is reported that berberine (BBR) can inhibit colorectal cancer (CRC). However, the mechanism of BBR on colon cancer is still unclear. Here, Chen Haitaoetal.studied the therapeutic effect of BBR on colon cancer from the perspective of intestinal microbiota and metabolic changes, which provided an overall perspective for understanding the effect of BBR on colon cancer. First, AOM/DSS mice were used as colorectal cancer animal models, and then the incidence of colorectal cancer in AOM/DSS mice after BBR administration was measured. 16S rRNA was used to study the composition and abundance of intestinal microflora. BBR significantly reduced the development of intestinal tumor, decreased the expression of Ki67 in visible polyps and intestinal tissue, and improved the morphology of colon in mice. In addition, BBR significantly changed the composition of intestinal microflora in AOM/DSS mice, which was characterized by a significant reduction ofArcanobacteriumCollinsandverrucousbacilliat the phylum level. At the genus level, it suppressed pathogenic species such asBacteriumrhusiopathiaesuis, and promoted some bacteria that produce short-chain fatty acids (SCFA), includingAlloprovella,FlavonifractorandOscillibacter[16].

2.3 PolyphenolsShan Shuhuaetal.studied the inhibitory effect and mechanism of ZSSP on colonitis-related cancer in mice. ZSSP reduced the number and volume of CAC polyps in mice in a dose-dependent manner and effectively limited AOM/DSS-induced organ damage in mice. The results of immunohistochemistry showed that ZSSP treatment could effectively prevent the increase of early CRC markers such as COX-II, EMR1 and Ki67 in CAC mice[17].

Damazo-Lima and Margarita evaluated the chemoprevention of SO and its phenolic AVA extract in AOM/DSS-induced colon cancer mice. Oat seeds germinated (at 25 degrees Celsius and 60% relative humidity for 5 d). After 16 weeks of administration, compared with AOM+DSS group (80%), the incidence of inflammatory grade, tumor (38%-50%) and glandular cancer (38%-63%) in SO and AVA treatment groups were significantly reduced. Both treatments normalized colonic GST and NQO1 activity and erythrocyte GSH levels, and significantly reduced β-GA in cecum and colon, indicating that intestinal parameters, inflammatory state and redox state of animals improved, so they played a superior role in chemoprevention[18].

2.4 SaponinsMiyoshi Noriyukietal.studied the effects of Evodia lepta and its main steroidal saponin diosgenin on the occurrence of colorectal cancer. After taking diosgenin and Evodia lepta, the incidence of colonic mucosal ulcer and dysplastic crypt induced by AOM/DSS was also significantly decreased, which was consistent with the fact that diosgenin and Evodia lepta significantly decreased the expression of AOM/DSS-mediated inflammatory cytokines such as IL-1β. In addition, the serum triglyceride level of mice decreased after administration, and it regulated antioxidant stress response and apoptosis-related genes, such as heme oxygenase-1, superoxide dismutase-3 and caspase-6[19].

Chen Lingetal.studied the role of total saponins of Panax notoginseng (PNS) in inflammation-related bowel cancer. PNS significantly reduced the occurrence and development of colonic tumor induced by AOM/DSS by reducing disease activity index (DAI) score and colonic tumor load. The 16srRNA data of fecal samples showed that the intestinal microbial community was obviously destroyed and PNS could restore the richness and diversity of intestinal microbial community. In particular, PNS could increase the abundance ofAkkermansia, which was significantly decreased in the model group, and negatively correlated with the progress of colon cancer[20].

2.5 Other classesKang Ju-Heeetal.studied the anti-proliferation and apoptosis mechanism of ergosterol peroxide in human colorectal cancer (CRC) cell line, and tested its anti-tumor effect on colonitis induced by AOM/DSS in mouse model. Ergosterol peroxide administration showed a tendency to inhibit the growth of colonic tumor in mice treated with AOM/DSS. Quantitative IHC staining showed that the Ki67 positive staining of colonic epithelial cells treated with hydrogen peroxide was significantly decreased and TUNEL staining was significantly increased in AOM/DSS treated mice[21].

Predes Daniloetal.identified chalcone agavins isolated from filamentous tequila as an inhibitor of Wnt/β-catenin pathwayinvitroandinvivo. Agavins destroyed the nuclear localization of β-catenin and inhibited the constitutive activity of TCF4 and dnTCF4-VP16. Embryological analysis of Xenopus laevis showed that agavins played an important role at the transcriptional level. In addition, agavins decreased tumor proliferation in colorectal cancer mice treated with AOM/DSS[22].

Jung Miaoetal.evaluated the inhibitory activity of vanillin on colonitis-induced colon cancer mice. After intraperitoneal injection of AOM and oral administration of DSS, different doses of vanillin were taken orally for 13 weeks. It was found that vanillin reduced the development of tumor induced by AOM/DSS. Compared with the model group, the total number of tumors in 100 mg/kg vanillin group decreased significantly, and gene expression analysis showed that vanillin could down-regulate the expression level of proteasome gene in colon tissue. 10 mM vanillin significantly inhibited the proteasome activity of HCT-116 cells by 41.27%. In addition, vanillin reduced the phosphorylation of mitogen-activated protein kinase (MAPK) and reduced the number of p65 positive cells, proliferating cells and granulocytes in colon tissue[23].

3 Discussion

At present, the pathogenesis of inflammatory bowel disease and its canceration is not clear, and there are a variety of causes, which are related to environment, heredity, gene mutation, inflammation,etc.One of the clear reasons is that inflammation-related bowel cancer is a kind of tumor caused by long-term inflammation. At present, most of the treatments focus on relieving symptoms, and there are many problems such as easy recurrence, increased drug resistance or many adverse reactions after drug withdrawal. At the same time, the chronic inflammatory state is likely to be transformed into colorectal cancer, so the treatment of traditional Chinese medicine has a great advantage. However, the study of traditional Chinese medicine compound prescription has many complex problems that are difficult to clarify, which makes it face many difficulties in going to the whole world. The active components of traditional Chinese medicine monomers have the advantages of clear structure, clear side effects, easy quality control,etc., and play an indispensable role in the treatment of diseases. Therefore, the research on the effective components of traditional Chinese medicine has become a trend of the modernization of traditional Chinese medicine research, which can clarify the efficacy and specific mechanism of the active components, explore its targeting effect, and further clarify the pathogenesis and drug action mechanism of inflammation-related bowel disease and its canceration.