Phytochemicals and Gastrointestinal Cancer: Cellular Mechanisms and Effects to Change Cancer Progression

Gastrointestinal (GI) cancer is a prevailing global health disease with a high incidence rate which varies by region. It is a huge economic burden on health care providers. GI cancer affects different organs in the body such as the gastric organs, colon, esophagus, intestine, and pancreas. Internal and external factors like smoking, obesity, urbanization, genetic mutations, and prevalence of Helicobacter pylori and Hepatitis B and Hepatitis C viral infections could increase the risk of GI cancer. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in fruits, grains, and vegetables. Consumption of phytochemicals may protect against chronic diseases like cardiovascular disease, neurodegenerative disease, and cancer. Multiple studies have assessed the chemoprotective effect of selected phytochemicals in GI cancer, offering support to their potential towards reducing the pathogenesis of the disease. The aim of this review was to summarize the current knowledge addressing the anti-cancerous effects of selected dietary phytochemicals on GI cancer and their molecular activities on selected mechanisms, i.e., nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), detoxification enzymes, adenosine monophosphate activated protein kinase (AMPK), wingless-related integration site/β-catenin (wingless-related integration site (Wnt) β-catenin, cell apoptosis, phosphoinositide 3-kinases (PI3K)/ protein kinase B AKT/ mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK). In this review phytochemicals were classified into four main categories: (i) carotenoids, including lutein, lycopene, and β-carotene; (ii) proanthocyanidins, including quercetin and ellagic acid; (iii) organosulfur compounds, including allicin, allyl propyl disulphide, asparagusic acid, and sulforaphane; and (iv) other phytochemicals including pectin, curcumins, p-coumaric acid and ferulic acid. Overall, phytochemicals improve cancer prognosis through the downregulation of β-catenin phosphorylation, therefore enhancing apoptosis, and upregulation of the AMPK pathway, which supports cellular homeostasis. Nevertheless, more studies are needed to provide a better understanding of the mechanism of cancer treatment using phytochemicals and possible side effects associated with this approach.

. Schematic illustration of seven selected mechanisms modulated by GI cancer. The figure is divided into seven columns and three rows. The column headings represent the pathways while the row headings represent target genes/proteins for each pathway (blue), the overview physiological effect of these genes on pathways (dark yellow), and changes occurring on these pathways modulated by GI cancer.  Figure 1. Schematic illustration of seven selected mechanisms modulated by GI cancer. The figure is divided into seven columns and three rows. The column headings represent the pathways while the row headings represent target genes/proteins for each pathway (blue), the overview physiological effect of these genes on pathways (dark yellow), and changes occurring on these pathways modulated by GI cancer.

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Phytochemicals have multiple health benefits for metabolic disorders such as cancer, cardiovascular disease, neurodegenerative diseases, and obesity [56]. Plants with a higher concentration of phytochemicals play a role in protection against free radical damage [57]. Research and clinical studies have postulated the anti-carcinogenic effects of phytochemicals, including their inhibiting of mitosis, inducing apoptosis, and enhancing the excretion of carcinogens [58]. In addition, phytochemicals possess both antioxidant and anti-inflammatory activities, where they interfere with several proinflammatory mediators [59].

Metabolism of Phytochemicals
Phytochemicals show variations in metabolism and deposition due to the variability in absorption, distribution, and excretion of phytochemical pharmacokinetics [60]. Examples of variational sources of phytochemicals include phase 1 metabolism in the liver where hydroxylation of phytochemicals can occur, resulting in novel secondary oxidation products [61]. Another example is metabolism by gut bacteria where phytochemicals undergo reduction, dehydroxylation, and demethylation, resulting in more biologically active metabolites [62]. In general, most phytochemicals present as glycosides or other conjugates in plant food, which means hydrolyzation is an essential process for absorption [63]. The hydrolysis could be achieved either by gut bacterial β-glucosidases in the colon or lower small intestine or by brush border membrane bound β-glucosidases [64]. After absorption, aglycones undergo extensive metabolism in the liver or gut epithelium with multiple compounds being conjugated by sulfotransferases (SULT) and UDP-glucuronosyltransferases (UGT) with glucuronic acid, glutathione, or sulfate, being potentially excreted in the bile or urine [65]. Compounds that are re-excreted through bile duct are deconjugated through bacterial β-glucuronidase, where they undergo enterohepatic recycling [64].

Search Strategy and Selection Criteria
Medline, Scopus, and PubMed were searched for papers published from 2000 using the search terms "phytochemical", "phytochemicals AND cancer", "phytochemicals AND colon cancer", "phytochemicals AND GI cancer", "phytochemicals subclasses AND cancer", "carotenoid AND GI cancer", "polyphenol and cancer", "prebiotics AND probiotics AND GI cancer", and "phytochemical AND metabolism". The search yielded approximately 6000 articles, and for this review, 237 articles were selected and analyzed.

Carotenoids
Carotenoids are pigments found in plants, bacteria, algae, and fungi [66]. The family of carotenoids (tetraterpenes) contains 500 compounds, 50 of which exhibit provitamin A activity [67]. While only 40 carotenoids have been identified in the human diet, human blood and tissue contain 20 carotenoids [68]. Carotenoids are well recognized for their antioxidant activities, regulation of cellular growth, immune response, and modulation of gene expression [69]. Pre-dominant carotenoids include lutein, lycopene, and β-carotene, which are abundantly found in egg yolk, tomato, and carrot [70].

Lutein
Lutein in an abundant fat-soluble xanthophyll with a singular molecular formula (C 40 H 56 O 2 ) [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, Biomolecules 2020, 10, 105 6 of 30 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
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 C 50 H 56 , 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].

β-Carotene
β-carotene, a core member of the carotenoid family, has been well documented for its natural antioxidant, anti-inflammatory, and anti-cancerous activity in recent years [93]. Carrot (Daucus carota L) is a popular root vegetable and an important dietary source of carotenoids [94]. The chemical composition of carrots includes moisture (86%), protein (0.9%), fat (0.2%), carbohydrate (10.6%), fiber (1.2%), total ash (1.1%), Ca (80 mg/100 g), p (53 mg/100 g), and Fe (2.2 mg/100 g) [95]. Carrots have been reported to inhibit the formation of neoplastic tumors in colonic cancer rat models, affecting the composition of low abundant gut microbiota like Lactobacillus reuteri [96]. Human cancer cells treated with 50 and 100 µg/mL or pentane fraction and 1:1 pentane: diethyl ether fraction have shown an inhibition in cellular proliferation due to induced sub G1 phase accumulation and enhanced apoptotic cell death [97]. Additionally, cancerous cells treated with carrot oil extract have reported an increase in BAX and P53 levels and a decrease in Bcl-2 levels ( Table 1) [98]. Studies have shown that carrots inhibit cellular proliferation and induce apoptosis and cellular arrest through the suppression of the MAPK/ERK and PI3L/AKT pathways (Figure 2) [99]. A study has reported that consumption of carrots is more effective in the prevention of gastric cancer in people at risk of the disease (those with a family history of gastric cancer) compared to other people. This suggests that following a healthy lifestyle could prevent the development of gastric cancer in people with higher risk [100]. . Phytochemicals as anti-GI cancer agents: mode(s) of action, aberrant signaling pathways (Wnt/β-catenin, detoxification enzymes, cellular apoptosis, PI3K/AKT/mTOR, AMPK, MAPK, and NF-κB), and pathway components targeted by phytochemicals (highlighted in green). Phytochemicals have a wide range of anti-cancerous actions through which one could target multiple mechanisms. These phytochemicals can enhance or suppress (green and red lines, respectively) the mechanisms through several activities. (see text for detailed mode(s) of action for phytochemicals mentioned).

Figure 2.
Phytochemicals as anti-GI cancer agents: mode(s) of action, aberrant signaling pathways (Wnt/β-catenin, detoxification enzymes, cellular apoptosis, PI3K/AKT/mTOR, AMPK, MAPK, and NF-κB), and pathway components targeted by phytochemicals (highlighted in green). Phytochemicals have a wide range of anti-cancerous actions through which one could target multiple mechanisms. These phytochemicals can enhance or suppress (green and red lines, respectively) the mechanisms through several activities. (see text for detailed mode(s) of action for phytochemicals mentioned).

Proanthocyanidins
Proanthocyanidins, also known as condensed tannins, result from flavanol condensation [101]. They are abundantly found as polymers and oligomers in fruits, barriers, seeds, leaves, and flowers [102]. Recent interest in proanthocyanidins has been stimulated due to their potential health benefits which arise mainly from their antioxidant activity [103]. The effectiveness of proanthocyanidins are determined by gut microbiome composition [104]. Additionally, they have anticancer properties via the reduction of tumor development by inducing apoptosis or inhibiting cellular proliferation [105].

Quercetin
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].

Ellagic Acid
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].

Organosulfur Compounds
Organosulfur compounds are sulfur-containing organic compounds with beneficial anti-inflammatory, antioxidant, and anti-cancerous effects [128]. Animal and epidemiological studies have shown that administration of organosulfur compounds reduces the risk of colorectal cancer through the induction of Biomolecules 2020, 10, 105 9 of 30 mitotic arrest and apoptosis [129,130]. Garlic, onion, asparagus, and cruciferous vegetables are abundant in organosulfur compounds.

Allicin
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].

Allyl Propyl Disulfide
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].

Asparagusic Acid
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, B 1 , B 2 , 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].

Sulforaphane
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].

Other Phytochemicals
The following four phytochemicals did not fit under any of the above categories, and, therefore, due to their beneficial anticancer effects, we decided to give them a section of their own.

Pectin
Pectin is a natural polysaccharide derived from the cell walls of plants like citrus fruits and apples consisting of a linear chain of and α-(1-4) linked D-galacturonic acid residues, with some of the galacturonic acid carboxyl group being methyl esterified [169]. Depending on the percentage of esterification, high methoxy pectin (more than 50%) or low methoxy pectin (less than 50%) can be formed [170]. Pectin has been proven to have multiple biological effects like the reduction of cholesterol, lipid, insulin, and sugar level in the body. In addition, pectin exerts anticancer activities [171]. Pectin has been used in the colon drug delivery carrier system as well as being conjugated with other drugs like cisplatin, thus enhancing the blood circulation of the drug in mice models [172,173]. Using pectin as a new anticancer oral drug delivery system will enhance antitumor efficacy and reduce the risk of systemic toxicity in colon cancer [174].
Gastric cancer cells treated with low molecular weight citrus pectin (LCP) have been found to suppress adhesion, aggregation, and metastasis of cancer cells [175]. Moreover, LCP decreases the activity of premetastatic protein GAL-3 resulting in the promotion of caspase-mediated apoptosis and inhibition of tumor cell growth [176]. Plant-based non-digestible carbohydrates like pectin show potential in reducing the risk of colorectal cancer through the inhibition of GAL-3 protein expression, thus enhancing apoptosis and inhibiting cancer cells migration [177]. Pectin extracted from potatoes has demonstrated a significant reduction in cellular proliferation of colon cancer cells through the suppression of intercellular adhesion molecule 1 (ICAM 1) expression [178,179].

Curcumin
Curcumin is an active phytochemical compound originating from the rhizomatous herbaceous perennial plant of the ginger family (Curcuma longa) [180,181]. Recently, curcumin has given more attention due to its multiple health benefits, especially with regard to the management of degenerative and inflammatory eye conditions [182]. Greater attention has been given to cancer and curcumin in recent years (21,098 articles have been published in PubMed in the last 10 years). Due to this huge number of articles, we decided to add the most important points in Table 1. In addition to this, we cite four articles we evaluated which discuss the correlation between GI cancer and curcumin and which have been published in the last two years [183][184][185][186].

p-Coumaric Acid
p-Coumaric acid is an aromatic phenolic compound found in navy beans (Phaseolus vulgaris), which are an economically and nutritionally important food crop worldwide [187]. Navy beans are rich in protein, carbohydrates, minerals, dietary fibers, vitamins, and many other polyphenolics structurally similar to p-coumaric acid [188]. They exhibit several beneficial health effects like anticancer and anti-microbial infection properties and anti-human immunodeficiency virus effects [189]. Rats fed with navy beans have shown a significant reduction in colon adenocarcinoma compared to controls. This significant reduction can be attributed to a (i) high level of butyrate production in the distal colon and (ii) a more controlled appetite, which reduces body fat significantly [190]. Dietary intervention in CRC survivors for four weeks has shown that the consumption of navy bean reduces the risk of CRC and other chronic conditions. In addition to this, results have measured how serum inflammatory markers can provide the chemoprotective effects of navy beans against CRC [191]. Navy beans and their metabolites (Table 1) have been implicated in the protection of CRC through the modulation of major metabolic pathways like lysine, sterol, amino and inositol, and fatty acid metabolism. Dietary intake of navy beans (35 g/day) has been found to increase the abundance of several amino acids in stools, showing a protective effect against CRC through the inhibition of cellular progression, reduction of oxidative stress, and induction of cellular apoptosis [192,193]. A study performed on 16 people (seven non-cancer subjects and nine CRC survivors) has shown that the addition of 35 g cooked navy bean powder in meals for 28 days is able to provide chemoprevention effects against CRC [194].

Ferulic Acid
Ferulic acid is a bioactive component found in rice bran [195]. Rice bran is one of the byproducts produced by the milling process of rice [196]. Great attention has been paid to rice bran recently due to its high nutritional value, potential to improve heath, low cost, and availability [197]. Bioactive and phytochemical compounds of rice bran, such as ferulic acid, have been reported to possess anti-inflammatory, anti-diabetic, anticancer, and antioxidant activities [198]. The oil present in rice bran contains specific bioactive compounds that are considered to have a cardiac friendly chemical profile [199]. Studies have shown that rice bran intake modifies intestinal microbiota, which helps to prevent CRC [200]. Additionally, rice bran exhibits antitumor activities through the modulation of multiple pathways like inhibition of oxidative stress and induction of apoptosis [201]. In vitro cancer studies have shown that rice bran and its bioactive compounds (Table 1) have been shown to inhibit carcinogenesis by suppressing chronic inflammation, blocking cell signaling, inhibiting proliferation, scavenging free radicals, and activating detoxification enzymes (Figure 2) [202][203][204]. The consumption of rice bran has been found to reduced the adenoma burden in APC min mice through the modulation of adiponectin which was observed to be significantly altered, thus playing a role in tumor suppression [205]. Administration of inositol hexaphosphate extracted from rice bran has been reported to significantly suppress β-catenin and COX-2 expression, which could inhibit the development of CRC [206,207]. In addition, human colorectal adenocarcinoma HT-29 cells treated with inositol hexaphosphate have been shown to induce apoptosis through the upregulation of BAX, caspase-3, and caspase-8 expression, and through the downregulation of Bcl-xl [208]. 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 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 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

Pro-anthocyanidins
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

Pro-anthocyanidins
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  [135,136] Allyl propyl disulfide

Bilberry
Glucuronidation O-methylation Peonidin-3galactoside * 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

Bilberry
Glucuronidation O-methylation Peonidin-3galactoside * 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]

Conclusions
Phytochemicals are biologically active compounds found in plants. They have illustrated anticancer activity against gastrointestinal cancer through the modulation of several mechanisms like inducing apoptosis, inhibition of oxidative stress and cellular progression, and blocking cellular signaling.

Challenges with Studying Phytochemicals
Although a lot of efforts have been spent to study the activities of phytochemicals as an anticancer agent, lots of limitations are linked to these studies. Firstly, the assessment of most of the studies performed has depended on an in vitro evaluation [209]. Most of the in vitro studies have been based on ethnopharmacological information where the selection of plants or phytochemicals occurs first, and then molecular-based approaches are used to emphasize the similarity between phytochemicals and approved drugs by comparing molecular structure and protein target cites and linking them to the potential health benefits [210,211]. These approaches are designed to study the anticancer effects of phytochemicals on specific phenotypes, which makes it difficult to analyze and generalize the health effects on the human body [212]. Secondly, lots of attention has been given to the positive effects of selective phytochemicals without any mention of the negative effects of other phytochemicals which could be potential carcinogens or tumor promoters [213].

Estimated Consumption Level of Phytochemicals
Phytochemicals are non-established nutrients with significant health promotion and protective effects [214]. When it comes to specifying the recommended phytochemical intake, several points need to be recognized: (i) the health benefits associated with phytochemicals cannot be attributed to a specific phytochemical compound, (ii) different biological activities make it hard to select a specific key biological role for phytochemicals and generalize this to the whole population, and (iii) there is no assigned disease or impaired function linked to one or any of the members of the phytochemical group [215]. Worldwide, efforts have been made to create an optimal consumption level for selected phytochemicals. A US study on twenty-six healthy participants showed that consumption of 13-22 g dietary fiber per day for 3 weeks reduces cholesterol levels by 7% [216]. The consumption level of phytochemicals varies between populations. For example, Italians consume 14.3 mg/day of total carotenoids while Americans consume 6.6-10.5 mg/day for men and 5.7-10.4 mg/day for women [217,218]. Studies have reported that consumption of lutein of up to 20 mg/day is safe and does not contribute to diverse side effects [219]. Limited information is available regarding the recommended dosage of phytochemicals due to many challenges. Firstly, there is limited information related to their bioavailability and heterogenicity. Secondly, there is limited information regarding the effects of food processing and dietary consumption on the effectivity of these flavonoids. Thirdly, differences in the absorbability of phytochemicals have been observed depending on the source of food [220].

Could Phytochemicals be Carcinogenic
Recently, more attention has been paid to secondary metabolites (phytochemicals) found in fruits and vegetables [221]. This has led to an increase in the consumption rate of these natural substances either in their natural form or as a supplement for medical purposes [222]. Many cancer patients use phytochemical supplements in combination with prescribed cancer treatments [223]. Despite the popular usage of phytochemicals, limited information is available regarding their toxicity and safety levels [224]. A number of phytochemicals found in people's food and seasonings have shown potential carcinogenic effects [225]. One example is capsaicin, a principle pungent component belonging to the genus Capsicum which is responsible for the hotness or intensity of chili peppers [226]. Multiple epidemiological studies suggest the protective role of capsaicin in cancer treatment [227]. Results from animal studies have reported the opposite, stating the carcinogenic effect of capsaicin [228]. These controversial results which have been obtained suggest caution when consuming these phytochemicals and that normalize and control studies are needed to prevent result discrepancies. Other examples of phytochemicals as potential carcinogens include cycasin, phytoestrogens, ptaquiloside, and safrole [229][230][231][232]. So far, no specific data are available to address the short-and long-term effects of phytochemical consumption and their potential as tumor promoters or carcinogens.

Could Phytochemical Combinations Have Synergistic Effects
The consumption of phytochemicals triggers multiple selected mechanisms, as highlighted in Table 1. Studies have shown that administration of cancer treatments combined with phytochemicals may improve the prognosis of the disease, as it affects multiple pathways [233]. If we could trigger multiple mechanisms by combining the consumption of multiple phytochemicals, will this improve cancer manifestations? For example, administration of lycopene triggers five mechanisms, namely, it downregulates the NF-κB pathway and Wnt/β-catenin, upregulates MAP-mediated protein kinase, detoxifies enzymes, and induces apoptosis. Will the administration of carrots which activate the two other mechanisms not activated by lycopene (PI3K/AKT/mTOR and MAPK) improve the anti-cancerous activities mediated by these secondary metabolites ( Figure 2)? Would this lead to a better outcome in which the action needed may be approached while the over-activation of mechanisms may be prevented?
Further research is needed to confirm the applicability of this suggestion, as well as the side effects of this combination, as there is little known about phytochemical/phytochemical interactions.

Phytochemicals in Cancer Drug Delivery
Cancer treatment with conventionally formulated anti-cancer drugs possesses multiple limitations like low solubility in water, short half-life in the body, poor specificity, and poor oral administration suitability [234]. Studies have shown enhancement effects when using phyto-nanotechnology on cancer cell lines [235]. This technology offers promising solutions for drug delivery systems by combining a phytochemical-based drug with a synthetic drug and then introducing the combination into the body [236]. Using nanotechnology in drug delivery increases bioavailability, decreases toxicity, prolongs circulation time, and improve efficacy [237]. More research is needed to confirm the positive effects of using this technology.

Final Thoughts
Phytochemicals found in fruits and vegetables have multiple beneficial effects on GI cancer. A diet rich in phytochemicals could improve the prognosis of GI cancer. Generally, the combination of phytochemicals could enhance anticancer effects by triggering multiple mechanisms, but more research is needed to support this promising means of enhancing cancer prognosis and possibly prevention. More attention needs to be paid to studying the bacteria involved in the biotransformation of phytochemicals to their metabolites, which could potentially help predict the health status of humans. Overall, a diet rich in fruits and vegetables is recommended.