Lutein in an abundant fat-soluble xanthophyll with a singular molecular formula (C₄₀H₅₆O₂) [71]. It is found abundantly in egg yolk, oranges, yellow fruits, and green leafy vegetables [72]. Lutein is one of the two carotenoids that accumulates in fovea in the human retina [73]. It is a major constitute of macular pigment which is responsible for fine feature vision [74]. Recently, lutein has gained public health attention due to its putative role in protection against degenerative eye conditions and cancer [75]. A study performed on a Korean population showed an association between dietary lutein and the risk of colorectal cancer [76]. Lutein has considerable antioxidant function, which regulates apoptosis [77]. Administration of lutein in animal models has been observed to decrease the concentration of K-ras and AKT in tumors, resulting in cell cycle arrest [78]. Mice treated with lutein have been found to significantly inhibit aberrant crypt foci (ACF) development in the colon, reducing cellular proliferation [79]. Additionally, administration of lutein has been observed to reduce β-catenin concentration, hyperplasia, and adenocarcinoma in colonic samples [80]. It also acts as an effective blocking agent by reducing the concentration of specific protein-like β-catenin involved in cellular proliferation and apoptosis (Figure 2) [81]. Moreover, lutein plays a role in reducing reactive oxygen species and oxygen radicals while enhancing DNA damage repair (Table 1) [82].

Lycopene is a lipophilic pigment and the main component of-red colored fruits and vegetables such as tomatoes [83]. Lycopene is structurally similar to β-carotene with the molecular formula C₅₀H₅₆, a hydrocarbon chain, and no functional groups [84]. The concentration of lycopene in tomatoes ranges 0.9 to 9.27 mg/g [85]. Lycopene is a potent antioxidant which can counteract reactive oxygen species like peroxyl radicals [86]. The expression of lycopene’s antioxidant activity is due to (i) the detoxification process through the production of enzymes like glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR); (ii) the inhibition of cytochrome P450 2E1, which is critical for the conversion of xenobiotics in cancer; and (iii) the suppression of carcinogen progression (Figure 2) [87]. In addition, lycopene exerts both anti-inflammatory and anti-cancer activity specifically against colorectal cancer [88]. Administration of lycopene using gold nanoparticles as a vehicle has been found to reduce the expression of pro-caspase 3, 8, and 9 and enhance Bcl-2-associated X protein (BAX) expression, thus enhancing the apoptotic pathway [89]. A one-day cultured colon cancer cell with 10 μm of lycopene showed a reduction in cellular growth by reducing the expression of Hmg Co-A reductase and enhancement in Ras translocation from the plasma membrane to cytosol [90]. Lycopene is reported to inhibit the expression of NF-κB and c-Jun N-terminal kinases (JNK), which (i) leads to a decreased tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and IL-6 and (ii) inhibits the expression of cyclooxygenase 2 (COX-2) and NO production (Table 1) [91]. In a gastric-induced carcinogens model, lycopene has been found to block the activity of carcinogenic cells through the upregulation of a reduced glutathione (GSH) dependent hepatic detoxification system, thus protecting cells from oxidative damage [92].

The cranberry (Vaccinium macrocarpon) is a fruit which has been used as a functional food due to its health benefits [106]. It is a rich source of polyphenols, which exerts anti-inflammatory, antiviral, antibacterial, antioxidant, anticarcinogenic, and antimutagenic activities [107]. It has a complex and rich phytochemical composition, consisting predominantly of A-type procyanidins (PACs), flavan-3-ols, anthocyanins, ursolic acid, quercetin, and benzoic acid [108]. Recently, the cranberry has received attention as a result of its effects related to lowering the risk of cancer [109]. Animal studies have reported the chemoprotective effect of cranberry to suppress the growth of several types of cancer cells, including colon, lung, prostate, oral, and ovarian [110]. Administration of 20% cranberry juice in water to rat models demonstrated a reduction in the total number of ACF [111]. Cranberry extracts have been reported to reduce proinflammatory interleukins and C-reactive protein [112]. APC^min/+ mice fed with 20% (w/w) freeze dried whole cranberry powder for 12 weeks showed a significant prevention of intestinal tumor formation (33.1%) due to induced cellular apoptosis and reduced cellular proliferation [113]. Also, it is reported that cranberry consumption inhibits the activation of the PI3K, AKT, and COX-2 signaling pathway (Table 1) [114]. Administration of cranberries has shown an activation in the AMPK pathway which helped maintain cellular homeostasis [115].

The bilberry (Vaccinium myrtillus L) is a rich natural source of anthocyanins [116]. Total anthocyanin content in the bilberry ranges from 300–700 mg/100 g [117]. It is classified by the American Herbal Products Association as a class 1 herb, which means it can be safely consumed when used appropriately [118]. Ellagic acid is a phenolic compound found in bilberry extracts which has potent antioxidant properties and can chelate metal ions and scavenge free radicals [119]. Treatment of rats’ hepatocyte primary culture with bilberries has shown a protective effect against oxidative damage [120]. Bilberries have been reported to induce phase II xenobiotic detoxification enzymes, which are critical for cancer prevention [121]. Additionally, bilberry-rich extracts have been observed to inhibit the growth of colon cancer cells but to not affect normal colon cells, thus suggesting a possible protective effect against cancer [122]. Rats with genetic colon adenoma fed concentrated bilberry extract (10% w/w) have shown a significant reduction in intestinal adenoma by 15–30% [123]. In a pilot study on 25 patients with colorectal cancer who were given bilberry extract for 7 days, the results showed a significant reduction in tumor cellular proliferation by 7% compared to the results before bilberry administration [124]. Treatment of human monocytic THP-1 cells with bilberry extract showed reduction in pro-inflammatory gene expression, interferon γ (IFN-γ), and cytokine secretion [125]. Moreover, bilberry extract exerts the ability to induce apoptosis and arrest growth in GI cancer (Figure 2) [126]. Bilberry extract has been reported to diminish topoisomerase catalytic activity in colon carcinoma cells, showing a protective DNA effect [127].

Attention has been given recently to garlic due to its high content of flavonoids and organosulfur compounds like allicin [131]. Worldwide garlic (Allium sativum) has been frequently used as a dietary botanical supplement [132]. Ally sulfur compounds like allicin found in garlic (1% of garlic’s dye weight) seems to be responsible for the beneficial effects of garlic [133]. Animal studies have shown that administration of garlic reduces the formation of ACF [134]. The mechanisms by which garlic inhibits the growth of carcinogen cells include reduction of DNA adducts, regulation of cellular arrest, activation of metabolizing detoxification enzymes, and induction of differentiation and apoptosis [135,136]. Organosulfur compounds present in garlic have shown potential for an anti-cancer drug by the modulation of epithelial growth factor receptor (EGFR), which plays a role in cell division [137]. Results obtained from an induced colitis mouse model have shown that administration of diallyl disulfide extracted from garlic is able to prevent the development of colitis-induced colorectal cancer [138]. In addition, garlic has been observed to prevent prolonged inflammation in mice, which supports the chemoprotective effect of garlic in CRC [139]. Moreover, consumption of garlic suppresses the activity of NF-κB by inhibiting phosphorylated P65 translocation (Figure 2) [140]. In xenograft nude mice, administration of S-allylmercaptocysteine (SAMC) in combination with rapamycin (a macrolide compound) was found to enhance anticancer ability by suppressing tumor growth and inducing apoptosis (Table 1) [141]. Administration of aged garlic extract in rat tumor models has been shown to attenuate colon tumor progression effectively by reducing cellular proliferation through the attenuation of NF-κB activity [142]. A meta-analysis study has indicated that the consumption of garlic is associated with reduced gastric cancer with a 95% confidence interval and a 0.53 odd ratio [143].

Chemical groups found in onions such as flavonoids, alk(en)yl cysteine sulfoxides (ACSOs), and allyl propyl disulfide are associated with the health benefits of onions [144]. The consumption rate of onion (Allium cepa L.) has increased worldwide, leading to an increase in the national production of onion by 25% over the last decade [145]. Compounds from onions have been reported to have multiple health benefits, including having antiplatelet, anticarcinogenic, and antithrombogenic activities [146]. Onion extracts have been reported to significantly induce apoptosis and reduce cellular proliferation in colorectal cancer [147]. An in vivo study has indicated that administration of onion in a hyperlipidemic colorectal cancer model plays a similar role to capecitabine in a colorectal cancer model without hyperlipidemia by inhibiting CRC and reducing hyperlipidemia [148]. Human cancer adenocarcinoma cells treated with 200 μm Se-methyl-L-selenocysteine (MSeC) for 24 h have been found to trigger 80% apoptosis in cells through endoplasmic reticulum stress rather than reactive oxygen species stress (Table 1) [149]. The benefit of onions is not limited to reducing or treating GI cancer but also to detecting cancer. One study used carbon nano onion films to develop a capacitive immunosensor for a CA19-9 cancer biomarker detector which succeeded in detecting CA19-9 in whole lysate colorectal adenocarcinoma using the sensor combined with information visualization methods [150].

Asparagus species are native medical shrubs which have beneficial medical properties and which belong to the Liliaceae family [151]. Major bioactive compounds found in asparagus include steroidal saponins, asparagusic acid, vitamins (A, B₁, B₂, C, E, Mg, P, Ca, and Fe), folic acid, asparagine, tyrosine, arginine, essential oils, tannin, resin, and flavonoids. The health properties of asparagus include anti-microbial, antioxidant, and cytotoxic activities [152]. Asparagus extracts have illustrated a potent cytotoxic effect against colorectal cancer [153]. Treatment of Myeloid-derived suppressor cells (MDSCs) with asparagus polysaccharide have shown a significant increase in apoptosis through intrinsic pathways and a significant decrease in cellular proliferation [154]. Old stems of asparagus (SSA) tested on colon cancer cells have been found to suppress cellular viability and block cellular migration and invasion through Rho GTPase signaling pathway modulation [155]. In human colon adenocarcinoma, methanolic extracts from white asparagus have demonstrated TRAIL death receptor pathway activation leading to the activation of caspase-8 and caspase-3, and, finally, to cell death. In addition, asparagus extracts have been seen to inhibit cellular pro-inflammatory mediators like MMP7, MMP9, and TNF-α [156].

Cruciferous vegetables refer to those which belong to the Brassicaceae family and include cabbage, broccoli, and Brussel sprouts [157]. This family is known for the glucosinolate, a sulfur-containing compound synthesized endogenously in plants derived from amino acid and glucose residues [158]. Upon cellular rupture through vegetable consumption, glucosinolates are hydrolyzed by endogenous enzymes and produce potential compounds such as thiocyanates and nitriles [159]. Cruciferous vegetables contain several phytochemical compounds such as sulforaphane. Studies have shown the beneficial effects of cruciferous vegetables which have helped inhibit the development of GI cancer [160]. In vivo and in vitro studies have demonstrated the ability of cruciferous vegetables to defend healthy cells against radiation and chemically-induced carcinogenesis [161]. Additionally, these vegetables have been shown to inhibit cellular proliferation, migration, and survival of tumor cells [162]. Cruciferous vegetables demonstrate antioxidant activity as they widely show a protective effect against oxidative stress through the depletion of glutathione [163]. Additionally, these vegetables induce acute oxidative stress through the inhibition of P38 MAPK, which inhibits Nrf2-Keap 1 dissociation (Table 1) [164]. Cruciferous vegetables guard against colorectal cancer through several mechanisms: (i) the modulation of detoxification enzymes (Figure 2), (ii) the induction of cellular apoptosis, and (iii) the controlling of cancer cellular growth through cell cycle arrest [165,166,167]. A meta-analysis study has shown that cruciferous vegetables significantly reduce the risk of gastric and colorectal cancer by 19% and 8%, respectively [168].

Phytochemical Subclass	Phytochemical and Structure	Dietary Source	Conversion Reaction	Metabolites Produced	Mechanism of Action	Model Used		References
						In Vivo	In Vitro
Carotenoids	Lutein	Egg yolk, kale, spinach, parsley, and peas	Oxidation	3′-dehydro-lutein	* Reduces slightly the risk of colorectal cancer * Reduces the risk of colorectal neoplasms in women * Inhibits the growth of carcinoma cells * Decreases the concentration of AKT expression which reduces cellular proliferation * Decreases β-catenin concentration thus enhancing the apoptotic pathway * Regulates miRNA expression through DICER 1 activity * Enhances DNA damage repair * Induces humoral and cell mediated-immune response * Scavenges against oxygen radicals * Quenches reactive oxygen species * Activates MAPK pathway through MAP3K9 interaction * Protects against the formation of colonic aberrant crypt foci	* Sprague-Dawley rats.	* Human normal colon epithelial cells * Human colon adenocarcinoma cells	[74,78]
	Lycopene	Tomato, guava, papaya, grapefruit, and watermelon	Auto-oxidation Radical-mediated oxidation	Apo-10′-lycopenoids	* Suppresses the progression of carcinogenesis through the inhibition of DNA synthesis * Inhibits cell invasion, metastasis, and angiogenesis * Reduces cell migration capacity * Downregulates AKT, NF-κB, MMP-2, MMP-7, and MMP-9 * Decreases β-catenin concentration * Reduces pro-inflammatory mediators and enzymes such as TNF-a and COX-2, respectively * Prevents oxidative damage through scavenging oxygen free radicals * Suppresses the expression of cyclin D1 and PCNA proteins * Inhibits the formation of colonic ACFs * Stimulates the activity of enzymes such as glutathione reductase, glutathione peroxidase, and glutathione S-transferase * Enhances apoptotic pathway * Activates MAPK signaling gene * Upregulates p21 cell cycle inhibitor protein	* Induced-colitis rat models * Sprague-Dawely rats * Fischer 344/NSIc rats	* HT-29 cell lines	[86,89]
	β-Carotene	Carrot	Oxidation	Falcarindiol 6-methoxymellein	* Inhibits the formation of neoplastic tumors * Reduces the number of polyps in the colon * Inhibits pleiotropic cytokines and the NF-κB pathway * Reduces the formation of macroscopic neoplasms by targeting low abundant gut microbiome * Inhibits cellular proliferation through MAPK/ERK and PI3K/AKT pathway inhibition * Enhances p53-dependent apoptosis pathway	* Azoxymethane (AOM) treated rats	* HT-29 cells * HCT 116 cells * CCD-33Co cells	[97,98,99]
Pro-anthocy-anidins	Quercetin	Cranberry	Sulfation Conjugation	3-(4hydroxyphenyl) -propionic acid hippuric acid catechol-O-sulfate	* Reduces small intestine tumor formation * Reduces inflammatory responses when consumed with fiber * Reduces tumor incidence, multiplicity, burden, and average tumor volume * Reduces colonic inflammatory cytokine expression such as IFN-γ and TNF-α * Inhibits the activation of the PI3K, AKT, and COX-2 signaling pathway * Inhibits cancer cell proliferation and tumor growth * Inhibits VEGF, MMP-2, and MMP-9 expression * Inhibits the incidence of AOM-induced ACF * Induces cellular apoptosis * Increases the number of colonic goblet cells and MUC 2 production * Increases caecal short fatty acids concentration	* Apc(min/+) mice * Male weanling rats	* HCT116 cell lines * HT-29 cell lines * Cancer cell line encyclopedia (CCLE)	[108,109]
	Ellagic Acid	Bilberry	Glucuronidation O-methylation	Peonidin-3-galactoside	* Reduces the expression of proinflammatory cytokines * Reduces inflammation and tumor development * Inhibits cellular proliferation * Inhibits the formation of colonic ACFs * Suppresses the activity of topoisomerase I and II which reduces DNA damage * Induces cellular apoptosis through NF-κB inhibition * Protective activities against colorectal cancer	* Female Balb/c mice	* Intraepithelial neoplasia * HCT-116 cell line	[120,121]
Organosulfur Compounds	Allicin	Garlic	Oxidation Hydrolysis	Allyl methyl sulfide (AMS) Allyl methyl sulfoxide (AMSO) Allyl methyl sulfone (AMSO2)	* Inactivates NF-κB localization by inhibiting glycogen synthase kinase 3 (GSK-3) which prevent colitis-induced colorectal cancer * Suppresses cellular proliferation and tumor growth * Induces colon cancer cell apoptosis * Anticancer activity against colorectal cancer through the modulation of epithelial growth factor receptor (EGFR) * Activates antioxidative transcriptor Nrf2	* Xenograft nude mice	* HCT-116 cell line	[135,136]
	Allyl propyl disulfide	Onion	Reduction	Quercetin 3,4‘-diglucoside Quercetin 4‘-glucoside	* Reduces cellular proliferation * Reduces migration rate of cancer cells * Reduces tumor growth rate in colorectal cancer * Induces cellular apoptosis * Induces cell cycle arrest at G2/M phase		* Caco-2 cell line * SW620 cell line	[146,147]
	Asparagusic acid	Asparagus	Sulfation	Asparagus polysaccharide dimethyl sulfide	* Cytotoxic effect against human colon cancer cell greater than 5-FU * Reduces cellular proliferation * Inhibits cell motility and cellular growth by targeting Rho GTPase signaling pathway * Induces intrinsic apoptosis through toll-like receptor 4 * Enhances the expression of BAX and Caspase 9		* HCT-116 cell line * Caco-2 cell line	[152,153]
	Sulforaphane	Broccoli, cabbage, Brussels sprout, and cauliflower	Hydrolysis	Thiocyanates Isothiocyanates Epithionitrile nitrile	* Reduces the risk of adenomatous polyps * Prevents colorectal cancer through miRNA modulation * Protects against Barrett’s esophagus * Induces apoptosis and cellular arrest * Induces detoxification enzymes * Cytoprotective effect through the induction of Nrf2 * Scavenges against free radicals		* Squamous cell carcinoma	[164,165]
Other Phytochemicals	Pectin	Apples, plums, oranges, and gooseberries	Colonic fermentation	Butyrate	* Inhibits cancer cell metastasis of gastrointestinal cancer * Inhibits colon cancer cell proliferation by downregulating ICAM1 expression * Induces apoptosis by downregulating Bcl-xL and Cyclin B * Modulates the expression of signature miRNA * Delivers oral drugs for colon cancer treatment	* BALB/c mice	* HCT116 cells * Caco-2 cell line	[169,170]
	Curcumin	Ginger	Hydrolysis	Curcumin glucuronide Curcumin sulfate	* Suppresses tumor growth by suppressing PPARγ pathway * Prevents cellular proliferation * Induces cellular apoptosis * Upregulates the expression of Caspase-3, cytochrome C, and BAX		* Cancer stem-like cells (CSC)	[183,184]
	p-Couramic acid	Navy beans	Hydrolysis	N-methylpipecolate 2-aminoadipate Piperidine Vanillate	* Reduces oxidative stress * Reduces the number of colonic aberrant cypt foci * Anti-tumor activity against colorectal cancer * Increases the abundance of amino acids, phytochemicals, and lipids in stool * Induces cellular apoptosis	* FVB/N mice		[189,190]
	Ferulic acid	Rice bran	Colonic fermentation	Tryptophan α-ketoglutarate γ-tocopherol/β-tocopherol γ-tocotrienol	* Inhibits cellular proliferation, cell cycle progression, and tumor growth * Decreases β-catenin and COX-2 in colon tumors * Increases the production of SCFAs * Induces nitric oxide synthase expression, Caspase-3 activation, and NF-κB pathway * Induces cellular apoptosis and lipid peroxidation * Scavenges free radicals * Modifies the composition of intestinal microbiota	* APC (min) mice	* Caco-2 cells * HAT-29 cells	[201,202]