Quercetin, a common flavonoid in plants, can induce G2 cell cycle arrest, inhibit angiogenesis and downregulate NF-κB expression due to its strong antioxidant and free radical scavenging properties (48). Quercetin-rich plants have been used to treat inflammatory diseases, tumors and hypertension (41). Previous studies showed that quercetin significantly reduced the number of intestinal adenomas (>2 mm 69%, 1–2 mm 79%) in APC^Min/+ mice (49). Velazquez et al (50) showed that quercetin may reduce the adenoma load of APC^Min/+ mice by inducing phosphorylation of plasma IL-6 and muscle signal transduction and transcriptional activator 3. In addition, quercetin significantly improved the decline of body function and metabolism in mice.

Kaempferol is found in a variety of plants and has been proven to have anti-inflammatory, antioxidant, antibacterial and antitumor activities (51). Kaempferol is associated with reduced incidence of various types of cancer, including skin, liver and gastric cancer (52). Kaempferol significantly reduces adenomatosis and tumor load in AOM/DSS mice and increases DACT2 gene expression in tumor tissues. β-catenin, CTNNB1 and LRP6 gene expression levels in CRC tissues were significantly inhibited by kaempferol-induced DACT2 repair. Similarly, kaempferol significantly increased gene expression of DACT2 in HCT116, HT29 and YB5, significantly decreased methylation of DACT2, and increased unmethylated DACT2 by 13.72 times. Further studies showed that the proliferation and migration of CRC cells are limited, and kaempferol could inhibit nuclear β-catenin and inactivates the Wnt/β-catenin pathway by directly binding DNA methyltransferase (DNMT) 1 (53).

Myricetin, as a natural dietary flavonoid compound, has the potential of enhancing immune regulation, inhibiting cytokine storm and antiviral, and has therapeutic effects on different types of tumors, inflammatory diseases, atherosclerosis, thrombosis and diabetes (54). Previous studies have shown that myricetin can reduce the number of adenomas in APC^Min/+ mice and reduce the number and degree of dysplasia in adenomas without any side effects. Myricetin selectively inhibits cell proliferation by downregulating Cyclin D1 and PCNA expression, and induces apoptosis of adenoma cells by downregulating Bax, c-Caspase-3, which may be related to the regulation of GSK-3β and Wnt/β-catenin pathways. Myricetin reduces the concentration of IL-6 and PGE2 in the blood. These results suggested that the mechanism of myricetin in treating adenoma may be the downregulation of phosphorylated p38MAPK/Akt/mTOR signaling pathway (55). Another study showed that myricetin significantly reduces the size and degree of small CRAs in AOM/DSS mice. In addition, myricetin significantly reduces the expression of inflammation factor TNF-α, IL-1β, NF-κB, p-NF-κB and COX-2 (56).

Isorhamnetin is one of the most important active components in Ginkgo biloba leaves, with antitumor, antibacterial, anti-inflammatory and antioxidant effects (57). Clinical studies have shown that intake of a diet rich in isorhamnetin is associated with a reduced risk of advanced adenoma recurrence (58), but the mechanism is unclear. A recent study reported that supplementation with an isorhamnetin diet significantly reduced the incidence of CRA, tumor number and load in AOM/DSS mice. Further studies demonstrated that isorhamnetin reduced DSS-induced inflammatory response, inhibited C-SRC activation and β-catenin nuclear translocation, and promoted the expression of c-terminal Src kinase (CSK), a negative regulator of the Src family of tyrosine kinases, which was also verified in vitro. In conclusion, the chemoprotective effects of isorhamnetin in adenomas are associated with anti-inflammatory activity, inhibition of carcinogenic Src activity, and loss of nuclear β-catenin (CSK-dependent activity) (59).

Anthocyanins are water-soluble flavonoids, whose stability is affected by pH, light, temperature and other factors (60). Studies have shown that anthocyanins can treat a variety of diseases, including neurodegenerative, cardiovascular and metabolic diseases and cancer, and regulate oxidative stress and intestinal microbiota (61). Freeze-dried Acai berry pulp (AP) is rich in cyanidin 3-rutinoside (C3R). In 1, 2-dimethylhydrazine and 2, 4, 6-trinitrobenzoic acid-induced male Wistar rats, intake of freeze-dried AP reduced adenoma proliferation, the incidence of high-grade intraepithelial adenoma, the total number of aberrant crypt foci (ACF) and ACF multiplicity. In addition, C3R (25 µM) has the potential to decrease RKO cell motility in vitro, and AP increases gene expression of negative cell proliferation regulators including Dlc1 and Akt3 (62). Fernandez et al (63) found that anthocyanins from a mixture of dehydrated blackberries and strawberries significantly reduced the number of CRAs in AOM/DSS mice and increased the total antioxidant activity of FRAP (plasma iron reduction capacity). Differences in colon microbiota before and after intervention were examined by 16S rRNA, which showed that anthocyanins could reduce the occurrence of adenomas by reducing the abundance of pro-inflammatory Bilophila wadsworthia population.

Freeze-dried black raspberry (BRB) powder reduced the rate of adenoma canceration in AOM/DSS mice. The number of pathogenic bacteria, including Desulfovibrio and Enterococcus, was significantly increased, while probiotics such as Eubacterium rectale, Faecalibacterium prausnitzii and Lactobacillus were significantly decreased in AOM/DSS mice, but BRB anthocyanin supplementation reversed this imbalance in the gut microbiome. BRB anthocyanins also cause demethylation of the SFRP2 gene promoter, resulting in increased SFRP2 expression at mRNA and protein levels. In addition, BRB anthocyanins downregulated the expression of DNMT31 and DNMT3B as well as P-STAT3. These results suggested that BRB anthocyanins may play a role in reducing the carcinogenesis rate of adenomas by regulating the composition of intestinal microbiota, changes in inflammation and methylation status of SFRP2 gene (64).

Another study showed that anthocyanin-containing purple-fleshed potatoes reduced the number of cells containing nuclear β-catenin (an indicator of colon CSC) by inducing mitochondria-mediated apoptosis and reduced adenoma incidence similar to sulindac in AOM/DSS mice. Further research showed that anthocyanin-containing baked purple-fleshed potato extracts inhibited proliferation and promoted apoptosis in colon CSCs in a p53-independent manner. It also inhibited the levels of Wnt pathway effector β-catenin (a key regulator of CSC proliferation) and its downstream proteins (c-myc and cyclin D1) and increased the levels of Bax and cytochrome C (proteins that mediate mitochondrial apoptosis) (65).

Anthocyanins from red grape pomace significantly reduced the adenoma load and the number of adenomas in APC^Min/+ mice, downregulated the expression levels of Ki-67, Akt and ERK proteins, and upregulated the expression of pERK, suggesting that Akt and pERK may be suitable biomarkers for the efficacy of anthocyanin target organs (66).

Kang et al (67) found that anthocyanins from red grape pomace may reduce the cecal adenoma load in APC ^Min/+ mice by inhibiting cyclooxygenase, and its inhibitory effect is more significant than sulindac. In addition, anthocyanins in cherry diet also significantly inhibited the proliferation of HT29 and HCT116, indicating that anthocyanins have favorable antitumor effects.

A previous study demonstrated that anthocyanin-rich bilberry extract reduces the occurrence of adenomas in AOM/DSS mice, and decreases inflammatory response and intestinal length reduction caused by inflammation (68). In addition, it has been revealed that anthocyanin-enriched Sweet Potatoes significantly reduced the number of adenomas in APC^Min/+ mice (69).

EGCG is the main catechin in green tea and has been shown to have a variety of pharmacological effects, including antioxidant, antitumor, anti-inflammatory, anti-microbial, anti-angiogenic, and cholesterol-lowering effects (70). EGCG was found to inhibit adenoma formation and reduce adenoma load in APC^Min/+ mice. BFGF protein degrades rapidly in the presence of EGCG, but this degradation is inhibited by proteasome inhibitors, while EGCG increases ubiquitin of bFGF and trypsin-like activity of 20S proteasome, leading to bFGF protein degradation. These results indicated that EGCG inhibition of adenoma is related to the decrease of bFGF expression (71). Similarly, Wang et al (72) showed that EGCG can reduce the adenoma load of AOM/DSS mice and reduce the number of ACF to delay the histological progression, and the intestinal microbiota structure is relatively stable during EGCG intervention, which may be the potential mechanism of EGCG inhibiting tumor.

Oligonol is a catechin oligomer extracted from litchi fruit, consisting of 17.6% of catechin-type monomers and 18.6% of proanthocyanidin dimers and trimers derived from grape seeds or lychee fruit with antioxidative and anti-inflammatory properties. A previous study showed that oligonol significantly inhibited the incidence and diversity of CRAs in AOM/DSS mice, and inhibited the activation of NF-κB and STAT3, as well as the expression of COX-2, iNOS and cyclin D1 in DSS-induced mice.

In addition, oligonol prevents oxidative stress-induced apoptosis of colon epithelial cells by attenuating lipid peroxidation (malondialdehyde) and protein oxidation (4-hydroxy-2-nonenal). Further studies showed that oligonol reduced the expression of IL-1β, TNF-α, IL-6, COX-2 and inosine in LPS-induced RAW264.7 cells. In another study, Ho-1, NQO-1, TRX 1 and GPX-2 antioxidant genes were upregulated by oligonol in intestinal epithelial CCD841CoN cells (73).

Naringin, a natural flavonoid, is rich in citrus fruits and has a wide range of pharmacological activities, including anti-inflammatory, anticancer, oxidative stress and genetic damage (74). A study evaluating the inhibitory effect of naringin on AOM/DSS mice found that naringin reduced the severity of CRAs by inhibiting myeloid-derived suppressor cells, pro-inflammatory mediators GM-CSF/M-CSF, IL-6 and NF-κB/IL-6/ST pathway in CRAs. Moreover, naringin can prevent ulcerative colitis and canceration induced by AOM/DSS without obvious side effects. Naringin-treated mice showed normal colorectal tissue structure and electron microscopic analysis showed that endoplasmic reticulum (ER) stress-induced autophagy was inhibited. Naringin inhibits the secretion of ER transmembrane proteins including GRP78 ATF6, IRE1, and activated PERK-phosphorylated EIF-2, as well as the autophagosome complexes ATG3, ATG5, ATG7, ATG12, ATG16 and ATG16L1 in intestinal mucosal cells. In conclusion, naringin prevents adenoma occurrence and progression by inhibiting ER stress-induced autophagy of mucosal cells in CRC (75).

Neohesperidin (NHP) is widely found in citrus fruits regulating intestinal microbiota (76) and regulating immunity (77). A recent study reported that NHP inhibits adenomatosis in APC^Min/+ mice, induces apoptosis and blocks angiogenesis in vivo. In the presence of NHP, the relative abundance of Bacteroidetes decreased, while the relative abundance of Firmicutes and Proteobacteria increased. In addition, fecal microbiota transplantation experiments further demonstrated that intestinal adenoma was significantly inhibited by feeding with NHP-treated fecal extract of mice, suggesting that changes in intestinal microbiota are the cause of NHP-mediated prevention of colorectal tumor (78).

Puerarin, a natural isoflavone extracted from Pueraria lobata, has potential antitumor, antioxidant and anti-inflammatory activities (79), but it has low solubility and low bioavailability. In a recent study, puerarin-loaded alginate microspheres (plams) were prepared by emulsion/internal gel method for the treatment of adenomas. Plams not only significantly reduced the inflammatory response by downregulating the expression of tumor-promoting cytokines TNF-α and IL-17A but reduced the occurrence of adenoma and carcinogenesis by inhibiting AOM/DSS-induced EMT in mice (80).

Isoliquiritigenin (ISL), a flavonoid with chalcone structure extracted from Glycyrrhiza uralensis, can activate the antioxidant system mediated by nuclear factor erythroid-2 related factor 2 (Nrf2) and negatively regulate nuclear factors-κB(NF-κB) and nod-like receptor thermal protein domain associated protein 3 (NLRP3) (81) and has significant antitumor effect (82). A previous study has shown that ISL can significantly reduce the incidence of intestinal adenomas and regulate the intestinal microbiota in AOM/DSS mice. 16S rRNA detection revealed that the structure of intestinal microbial community in AOM/DSS mice changed significantly, the level of Bacteroidetes decreased, and Firmicutes increased. High dose ISL (150 mg/kg) reversed the imbalance at phylum level and changed the diversity composition of the intestinal microbiota, in which the abundance of Helicobacter increased, while the abundance of Lachnospiraceae and Rikenellaceae decreased. At the genus level, ISL reduced the abundance of opportunistic pathogens (E. coli and Enterococcus) and increased the level of probiotics, particularly butyrate-producing bacteria (Coccidioides butyricus, Clostridium and Ruminococcus). In addition, ISL decreased IL-6, IL-10, TNF-α, IL-1 β and COX-2 expression, suggesting that ISL may have a synergistic effect with intestinal microbiota in protecting AOM/DSS mice (83).

Lonchocarpin is a Wnt/β-catenin pathway inhibitor isolated from Lonchocarpus sericeus, which is cytotoxic to neuroblastoma and leukemia cell lines (79). A recent study demonstrated that lonchocarpin could reduce the proliferation of adenoma cells in AOM/DSS mice and significantly reduce the proportion of Ki-67 and BrdU positive cells in the tumors of mice without any toxicity (84). Further studies showed that lonchocarpin inhibited nuclear localization of β-catenin and constitutive active form of TCF4-dnTCF4-VP16. Embryological analysis of Xenopus laevis showed that lonchocarpin plays a role at the transcriptional level. In addition, lonchocarpin inhibited cell migration and proliferation in HCT116, SW480 and DLD-1 CRC cell lines, without any detectable effect on the non-tumorigenic intestinal cell line IEC-6 (84).

Milk thistle, a flavonoid antioxidant compound mainly composed of silibinin, is a key regulator of CDK4 cell cycle. When CDK4 becomes active by binding to cyclin D1, it allows cells to enter the G1 phase of the cell cycle, and enters the S phase by phosphorylating retinoblastoma protein. APC mutation, which functions by activating CDK4 pathway, plays a key role in the early stage of intestinal tumorigenesis (85). A previous study demonstrated that silibinin inhibits cell proliferation in vivo and in vitro and leads to G1 arrest of cell cycle (regulated by CDK4 pathway) (86). It was also identified that silibinin could significantly reduce the size and number of adenomas in APC^Min/+ mice, and significantly reduce the expression of CDK4 and Ki67 pathway components in the epithelium (87). In the study of Barone et al (88), the role of silybin has been confirmed. Silybin is the main component of silymarin (SIL). Estrogen receptor beta (ERβ) is considered to be gradually decreased in human adenoma-cancer sequence, and ERβ deficiency increases small intestinal tumorigenesis in rodents.

ERβ selective agonists SIL and/or lignin (LIG) were added to APC^Min/+ mice, and even a specific combination of SIL and LIG significantly counteracted the occurrence of intestinal adenomas and increased ERβ mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration was accelerated, which was similar to that of wild-type mice (88).

Scutellarin is a flavonoid isolated from Scutellaria baicalensis, which has the effects of anti-inflammation, antioxidation and regulating immunity (89). A recent study has shown that scutellarin inhibits adenoma carcinogenesis and alleviates pathological symptoms in AOM/DSS mice. Scutellarin decreased the concentration of serum TNF-α and IL-6, increased the expression of Bax and decreased the level of Bcl-2 in adenoma by downregulating the cascade of Wnt/β-catenin signal, which was verified in vitro. It was suggested that scutellarin can prevent the carcinogenesis of adenoma by reducing the cascade of Wnt/β-catenin signal (90).

Radix Tetrastigma hemsleyani flavone (RTHF) is the main component of the root of Radix Astragali, which has been shown to have anti-inflammatory, analgesic, antiviral and immunomodulatory effects (91). Wu et al (92) found that RTHF can reduce the number and size of intestinal adenomas and prevent adenoma carcinogenesis in AOM/DSS mice, and RTHF can reduce cell proliferation, induce cell cycle arrest in G0/G1 phase and inhibit epithelial-mesenchymal transition in a dose-dependent manner. In addition, RTHF inhibits the expression of Lgr5, c-Myc and Cyclin D1 in tumor tissues. In conclusion, the inhibition of CRA by RTHF is related to the decrease of the activity of Wnt/β-catenin pathway and the downregulation of target gene expression (92).

Spinosin exists widely in Ziziphi Spinosae semen (ZSSP), which has the effects of anti-inflammation and antioxidant stress, and has a favorable curative effect on colitis, anxiety and sleep disorder (93,94). The water-soluble polyphenols extracted from ZSSP have significant anti-colorectal tumor activity, including inhibiting cell proliferation and promoting cell apoptosis (95). In AOM/DSS mice, ZSSP reduced the number and volume of adenomas in a dose-dependent manner, inhibited the carcinogenesis of adenomas and reduced AOM/DSS-induced organ damage in mice. Immunohistochemical analysis demonstrated that ZSSP could downregulate the expression of COX-2, EMR1 and Ki67. Further studies showed that spinosin was identified as an antitumor component of ZSSP by the macroporous resin of SP207 and RP-HPLC-MS/MS (96).

Polymethoxyflavones (PMF), a family of natural compounds containing nobiletin, hesperidin, heptamethoxyflavonoids and tetramethoxyflavonoids, are found almost exclusively in citrus plants (97). PMF is higher in pericarp than in other edible parts of fruit and has a wide range of biological activities, including antioxidant, antitumor and anti-inflammatory (98). A previous study reported that PMF significantly inhibits the formation of BaP/DSS-induced CRAs by regulating BaP metabolism and reducing BaP mutagenic metabolites and DNA adducts, and downregulates the expression levels of IL-6, IL-10, TNF-α, COX-2, MCP1 and CXCL-1 to alleviate inflammation. The results of RNA-sequencing (RNA-seq) showed that PMFs improved the abnormal molecular mechanism induced by BaP/DSS, including activating inflammation, downregulating antioxidant targets and inducing transfer genes. Autophagy defects caused by BaP/DSS-induced tumorigenesis were improved by PMF. In addition, PMFs also changed the composition of intestinal microbiota, increased butyrate-producing probiotics and reduced tumor-related bacteria (99).

Coumestrol is a kind of phytoestrogen and belongs to flavonoids. Previous studies have shown that ovariectomy increased the number of intestinal adenomas in APC^Min/+ mice by 77%. Replacing estradiol (E2) in ovariectomized APC^Min/+ mice reduced the number of adenomas to baseline levels and upregulated the expression of estrogen receptor beta (ERβ). A previous study revealed that coumestrol significantly inhibited the volume of intestinal adenomas in ovariectomized APC^Min/+ mice. Moreover, coumestrol improved the damage of E-cadherin and β-catenin and upregulated the protein expression of ERβ (100).

Genistein, an isoflavone found in soybean, can inhibit inflammation, promote apoptosis and regulate steroid hormone receptors (101). It has been found that genistein reduces the number of adenomas at the same level as non-ovariectomized mice (100). Genistein 27 (GEN-27), a derivative of genistein, protects mice from adenoma carcinogenesis induced by AOM/DSS, reduces the number and volume of adenomas and reduces the mortality of mice. Furthermore, GEN-27 increased the expression of APC and AXIN2 and decreased the nuclear localization of β-catenin, which was due to the inhibition of nuclear localization of NF-κB/p65 and upregulation of CDX2. Moreover, GEN-27 decreased the binding of p65 to CDX2 silent region and increased the binding of CDX2 to APC and AXIN2 promoter regions, thus inhibiting the activation of β-catenin induced by TNF-α. In addition, GEN-27 significantly decreased the secretion of proinflammatory cytokines and macrophage infiltration. The results showed that the anti-proliferation effect of GEN-27 is mediated by p65-CDX2-β-catenin pathway through the inhibition of β-catenin target gene (102).

Bergamot is a typical plant produced in Italy, and its fruit is mainly used to extract essential oil. It was previously identified that flavonoid-rich extract from bergamot juice (BJe) has antitumor effects (103), which is related to the fact that BJe can interfere with intracellular signaling pathways related to tumor initiation, promotion and progression (104). It has been found that Bje has antioxidant and anti-inflammatory activities in vitro and in vivo (105). BJe (35–70 mg/kg) significantly reduced the number of colonic and small intestinal adenomas in Apc mutant rats, and the mucin depletion foci of colon premalignant lesions showed a significant dose-related decrease.

It should be noted that BJe of 70 mg/kg significantly downregulated inflammation-related genes (COX-2, iNOS, IL-1 β, IL-6, IL-10 and Arginase1), induced apoptosis, significantly upregulated p53 and survivin, and downregulated p21 gene expression in rat colon tumors. It is suggested that the inhibitory effect of Bje on adenoma is partly due to its pro-apoptotic and anti-inflammatory effects (106).

Daphne genkwa Sieb. et Zucc. is a famous medicinal plant, and total flavonoids of Daphne genkwa (TFDG) are the active ingredient. In Apc^Min/+mice, the number and diversity of colonic adenomas decreased significantly after TFDG treatment, and the life span of mice was significantly prolonged. TFDG significantly downregulated the expression of IL-1α, IL-1β, IL-6, IL-10 and G-CSF in intestinal tissue and serum, and downregulated the expression of IL-2, IL-12, IFN-γ and TNF-α in serum. These results suggested that the effect of TFDG may be related to its ability to regulate immunity and inhibit the production of inflammatory cytokines (107).

CUR is a bioactive component derived from the rhizome of turmeric. It has been shown to exert anti-inflammatory and antitumor properties by interacting with several molecular targets, including transcription factors, enzymes, cyclins, cytokines, receptors and adhesion molecules (108). Girardi et al (109) showed that a diet rich in CUR could reduce the total number and average size of adenomas in APC^Min/+ mice. In the high CUR diet group, the number of atypical hyperplasia and CRC decreased significantly, and CUR significantly upregulated caspase3 and downregulated the level of Cyclin D1 (109). COX2 is one of the most important molecules involved in tumorigenesis. High expression of COX-2 can be detected in adenomas (110,111). CUR can reduce the size and number of adenomas by significantly inhibiting the mRNA and protein expression of COX2, but does not inhibit the expression of COX1 (112,113). In addition, CUR may play a role in the treatment of adenoma by inhibiting the expression of pro-inflammatory cytokines IL-1 β, IL-6 and Cox-2 and downregulating Axin2 in Wnt/β-catenin signal pathway (114). McFadden et al (115) showed that CUR increased the abundance of intestinal bacteria in AOM mice, prevented the decrease of age-related alpha diversity, increased the relative abundance of Lactobacillus, and reduced or eliminated the load of CRAs, indicating that the beneficial effect of CUR on tumorigenesis is related to the maintenance of more diverse intestinal microecology. CUR has the disadvantage of being insoluble in water due to its high hydrophobicity. Adachi et al (116) used surface control technology to form submicron particles of CUR, which significantly improved its water solubility, and this derivative was named Theracurmin. Treatment with 500 ppm Theracurmin for 8 weeks inhibited the development of intestinal adenoma and did not change the transcriptional activity of NF-κB promoter, but inhibited the expression of MCP-1 and IL-6 mRNA, the downstream target of NF-κB (116). Seiwert et al (117) also confirmed the therapeutic effect of CUR on adenomas. Compared with the control group, the number of adenomas in mice treated with micellar CUR (mCUR) decreased significantly. No side effects were observed in animals that received mCur daily for at least three months (117).

Turmerone (TUR) is another compound of turmeric, which is composed of five structure-related sesquiterpenes including ar-TUR. A study of combination therapy showed that both TUR and CUR could inhibit the expression of iNOS and COX-2 in AOM/DSS mice induced by LPS. Tracing experiments with actinomycin D showed that CUR accelerated the decay of iNOS and COX-2 mRNA and prevented LPS-induced HuR translocation, which indicated that there was a post-transcriptional mechanism. In AOM/DSS mice, TUR significantly inhibited the diversity of adenomas, the combination of CUR and TUR eliminated tumor formation, and oral TUR significantly inhibited colorectal shortening by 52–58% (118).

Another study on the treatment of AOM/DSS mice with CUR combined with ASA showed that CUR significantly inhibited the occurrence and development of adenoma in a dose-dependent manner compared with ASA. RNA-seq revealed that compared with the single treatment, the low-dose combination of CUR and ASA could downregulate the protein expression of Alb and Mfap4, and upregulate the mRNA expression of Krt36, Tacstd2, Hoxd10 and Hoxd13. These differentially expressed genes are located in several classical pathways in adenomatous inflammatory carcinogenesis and liver metastasis of CRC (119). Another study of 3,3-diindolylmethane (DIM) combined with CUR in the treatment of tumors in F344/NTac-Apc^am1137 Pirc rats showed that DIM and CUR significantly decreased the number and severity of CRAs and increased apoptosis in mucosa. In addition, a slight decrease in Survivin-Birc5 expression was observed in all treatments compared with the control group (120). Lev-Ari et al (121) have shown that physiological dose of celecoxib (5 µmol/l) inhibits cell proliferation and promotes apoptosis through COX-2-dependent and independent pathways in the presence of 10–15 µmol CUR, thus inhibiting the growth of CRAs.

RSV (3,4,5-Trihydroxy-trans-stilbene) is a kind of natural polyphenol with antioxidant, anti-inflammatory and anticancer properties, which is well absorbed in vivo and metabolized rapidly and widely (122). Studies have shown that RSV significantly reduces the number of adenomas in AOM/DSS mice (123). RSV combined with grape seed extract (RSV-GSE) significantly inhibited the occurrence of intestinal adenoma in AOM/DSS mice without any gastrointestinal toxicity. RSV-GSE reduced the number of crypts containing nuclear β-catenin by inducing apoptosis. In vitro, RSV-GSE inhibited Wnt/β-catenin pathway, c-Myc and cyclin D1 protein levels, but sulindac did not. RSV-GSE also induces mitochondrial-mediated apoptosis in colonic CSC, which is characterized by p53, increased Bax/Bcl-2 ratio and PARP cleavage. In addition, short hairpin RNA-mediated knockdown of p53 (a tumor suppressor gene) in colonic CSC did not change the efficacy of RSV-GSE (124). Saud et al (125) constructed APC^CKO/Kras^mut mice to study the antitumor effect of RSV. They found that adding 150 or 300 ppm RSV to mice inhibits 60% of tumorigenesis. In 40% of the mice with tumors, the expression of Kras was lost and the expression of miR-96 was increased. MiR-96 is a miRNA previously shown to regulate Kras translation. The results showed that RSV could prevent the formation and growth of colorectal tumors by downregulating the expression of Kras.

Honokiol (HNK) is a lignan that inhibits the proliferation, invasion and survival of numerous human cancer cell lines. HNK exerts its antitumor effect by regulating the main checkpoints, including NF-κB, STAT3, m-TOR and EGFR (126). A recent study showed that HNK decreased the number and volume of adenomas in AOM/DSS mice, and significantly decreased the expression of YAP1, TEAD1 and stem cell marker proteins. In vitro experiments revealed that HNK could inhibit the proliferation and colony formation of tumor cells and induce apoptosis. In addition, HNK inhibited the activity of DCLK1 kinase and the expression of LGR5, CD44, and inhibited Ser127 phosphorylation in YAP1 (127). Another study demonstrated that the therapeutic effect of HNK on APC^Min/+ mice is highly related to citric acid cycle, pentose phosphate pathway, pyrimidine, tyrosine, arginine, proline and glutathione metabolism (128).

Sesamol is a common lignan in sesame, which can mediate anti-inflammatory effects by downregulating the transcription of inflammatory markers including cytokines, redox status, protein kinases and pro-inflammatory enzymes. Sesamol also induces apoptosis and activates caspase cascades through mitochondria and receptors (129). Shimizu et al (130) found that sesamol could reduce the number of polyps in the middle small intestine of APC^Min/+ mice, and sesamol downregulated the expression levels of COX-2, cPGES, mPGES2, EP1 and EP2 genes in polyps. In addition, sesamol did not inhibit the expression levels of COX-1 and EP4 mRNA in non-polyps and intestinal polyps. In the aforementioned study, in vitro experiments demonstrated that the basal cyclooxygenase-2 transcriptional activity decreased by 50% under 100 µM sesamol through the β-galactosidase reporter gene system, suggesting that sesamol may play an antitumor role as a cyclooxygenase-2 inhibitor (130).

Caffeic acid phenethyl ester (CAPE) is a phenolic antioxidant extracted from propolis (bee resin) and a kind of catechol. It has been reported that CAPE has strong anti-inflammatory activity, which can significantly reduce the size, number and load of adenomas in AOM/DSS mice, alleviate intestinal atrophy and increase the length of colon in a dose-dependent manner. CAPE decreased the activation of NLRP3 inflammatory bodies in BMDMs and THP-1 cells. Further studies have shown that CAPE regulates NLRP3 at the post-transcriptional level by inhibiting the production of ROS. However, CAPE does not affect the transcription of NLRP3 or IL-1β, but enhances the binding of NLRP3 to ubiquitin molecules and promotes the ubiquitin of NLRP3. Notably, CAPE suppressed the interaction between NLRP3 and CSN5, but enhanced the interaction between NLRP3 and Cullin1 (131).

Oleuropein, the main phenolic active ingredient of Olea europaea (Oleaceae), belongs to catechins. It has been proven to have the effects of anti-oxidation, antitumor, anti-inflammation, neuroprotection and liver protection. Oleuropein can effectively inhibit the progression of esophageal, gastric, lung and liver cancer (132).

A previous study has shown that oleuropein can inhibit the occurrence and diversity of CRA, improve adverse symptoms, and DAI score, downregulate the expression of IL-6, IFN-γ, TNF-α and IL-17A, and reduce the expression of COX-2 and PCNA. In addition, oleuropein significantly downregulated NF-κ B, Wnt/β-catenin, P3IK/Akt and STAT3, and decreased the expression of CD4 (+) Roγ t (+) IL-17 (+) IFN-γ (+) T cell subsets and IL-17A and IFN-γ in lamina propria (133).

Cranberry contains a variety of ingredients related to human health. Studies have shown that cranberry polyphenol extract significantly decreased the incidence of adenoma and canceration rate induced by AOM/DSS, reduced the size of adenoma and downregulated the expression of IL-1β and IL-6, TNF-α in mice (140). Walnut phenolic extract significantly reduced the development of adenoma induced by AOM/DSS, reduced IκB phosphorylation/degradation and NF-κB DNA binding activity induced by TNF-α, and decreased NF-κB signal transduction in colon (141). Polyphenols extracted from Annurca significantly reduced the number of adenomas in colon and small intestine, slowed down weight loss and severe rectal bleeding in Apc^Min/+ mice, increased antioxidant activity and upregulated DNA methylation in mice (142).