Table 3.
Anti-CRC effects and mechanisms of action of phenolic compounds based on in vivo studies.
| Phytocompound | Source | Animal Model Studied | Dose and Route of Administration | Mode of Action | Reference |
|---|---|---|---|---|---|
| Flavonoids | |||||
| 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside | Polygonum multiflorum Thunb | AOM-induced colon carcinogenesis in male F144 rats | Oral administration, 30, 150, 250 mg/kg | Decreased the number ofACF by 47–54%; suppressed tumor growth; downregulated NF-κB in nucleus and cytoplasm; downregulated CEA | [170] |
| 4′-hydroxychalcone | Herb, teas, and spices | APCMin/+ mice | Oral administration, 10 mg/kg | Reduced the incidences and size of adenomas; induced apoptosis; suppressed proliferation of polyps; downregulated Ki-67; downregulated c-Myc, Axin2 and CD44 gene expression | [171] |
| Aciculatin | Chrysopogon aciculatus | HCT116 induced tumor xenograft SCID mice | Intraperitoneal injection, 30 mg/kg | Suppressed tumor growth without losing weight; upregulated the expression of p53 and downregulated the expression of Ki-67; induced apoptosis; arrested cells in sub G1 phase | [172] |
| Apigenin | Parsley, wheat, onions, apples, and tea plants |
AOM-induced CF-1 mice and Min mice carrying mutant APC gene | Oral administration of 0.1% dietary apigenin | Reduced ACF formation and ODC activity | [173] |
| Male BALB/c-nu mice | Intraperitoneal injection, 20 mg/kg | Induced apoptosis of CRC cells; upregulated FADD expression and its phosphorylation | [174] | ||
| Male BALB/c-nu mice injected with SW480 cells | Route of administration not reported, 50 mg/kg | Elevated transgelin and downregulation of MMP-9 expression via reducing Akt phosphorylation at Ser473 and Thr308 | [175] | ||
| APCMin/+ mice | Oral gavage, 25 and 50 mg/kg | Reduced the number of polyps; induced of p53 activity | [176] | ||
| Nude BALB/c mice injected with HT-29 cells |
Subcutaneous injection, 35 mg/kg | Induced apoptosis; induced autophagy through inhibition mTOR/PI3K/Akt signaling pathway | [177] | ||
| SCID mice | Oral gavage, 25 mg/kg | Suppressed prosurvival regulators Mcl-1, Akt, and ERK | [178] | ||
| NEDD9 knock downed DLD1 cells mediated metastasis model in female athymic nude mice | Intraperitoneal injection, 20 mg/kg | Suppressed invasion, migration, and metastasis by downregulating overexpressed Neural precursor cells expressed NEDD9 | [179] | ||
| Baicalein | Scutellaria baicalensis Georgi | AMO and DSS induced colon tumor in male ICR mice | Oral administration, 1,5 and 10 mg/kg | Restored colon length; reduced tissue inflammation. | [180] |
| SW620 xenograft in BALB/c nude mice | Intraperitoneal injection, 50 mg/kg | Suppressed tumor growth by 55% without losing body weight | [181] | ||
| CT-26 derived tumor in female BALB/c mice | Intraperitoneal injection, 20 and 40 mg/kg | Reduced tumor growth rate; downregulated TLR4 and p-IκBα protein expression; inhibited NF-κB | [182] | ||
| HT-29 cell-induced tumor xenograft in male nude mice | Oral administration, 10 mg/kg | Suppressed tumor growth by 29.33% compared to the control group; induced apoptosis; upregulated p53 and p21 | [183] | ||
| DLD-1 tumor xenograft in BALB/c athymic nude mice |
Intragastric administration, 20 mg/kg | Suppression of tumor growth; inhibition of ERK phosphorylation; downregulation of MMP-2 and MMP-9 | [184] | ||
| HCT116 tumor xenograft in NSG immunodeficient mice | Intraperitoneal injection, 50 mg/kg | Suppressed tumorigenesis; inhibited colon cancer growth; induced apoptosis and senescence | [185] | ||
| HCT116 tumor xenograft in athymic BALB/c nude mice | Intraperitoneal injection, 80 mg/kg | Suppressed tumor growth; induced senescence; upregulated DEPP; activated Ras/Raf/MEK/ERK pathway | [186] | ||
| HT-29 tumor xenograft in nude mice | Intraperitoneal injection, 50 and 100 mg/kg | Suppressed tumor growth | [187] | ||
| HCT116 tumor xenograft in athymic BALB/c nude mice | Intraperitoneal injection, 100 and 200 mg/kg | Suppressed tumor growth; induced apoptosis; suppressed cancer stem cells; inhibited EMT and cyclin D1 | [188] | ||
| APCMin/+ mice | Oral administration, 30 mg/kg | Reduced tumor numbers; suppressed IL-1β, IL-2, IL-6, and IL-10 | [189] | ||
| HCT116 tumor xenograft in male BALB/c nude mice | Intraperitoneal injection, 100 mg/kg | Suppressed tumor growth; decreased circMYH9, mir761 and HDGF | [190] | ||
| Boeravinone B | Boerhaavia diffusa | DMH-induced CRC in Swiss albino Wistar rats | Intraperitoneal injection, 20 and 40 mg/kg | Decreased the number of tumor incidences; downregulated LPO; upregulated catalase, SOD and GSH; downregulated TNF-α, IL-1β, IL-6, COX-2, PGE2 and iNOS; upregulated levels of IL-4 and IL-10; down regulated MPO; downregulated the expression of GDI2 mRNA | [191] |
| Chrysin | Passiflora caerulea, Passiflora incarnata, Oroxylum indicum | AOM-induced ACF in male F344 rats | Dietary administration, 0.001% and 0.01% | Reduced mitotic index and increased apoptotic index; reduced the frequency of ACF | [192] |
| Male albino rats injected with DMH + DSS | Oral administration, 125 and 250 mg/kg | Reduced the level of CXCL1, AREG and MMP-9 | [193] | ||
| Curcumin | Curcuma longa | DSS-induced colitis in C57BL/6 mice | Oral consumption as dietary supplement, 0.6% | Reduced tumor incidences; inhibited nuclear translocation of β-catenin; downregulated TNF-α and interferon-γ; downregulated COX-2 and p53 | [194] |
| HCT116 tumor xenograft in female ICR SCID mice | Intragastric administration, 500 mg/kg | Suppressed tumor growth; inhibited proteasome; suppressed proliferation; induced apoptosis | [195] | ||
| AOM-DSS induced CRC in male C57BL/6 mice | Oral gavage, 500 mg/kg | Reduced CRC tumor number; downregulated IL-1β, IL-6, COX-2 and β-catenin; suppressed Axin2 by inhibiting Wnt/β-catenin pathway | [196] | ||
| AOM-induced colonic preneoplastic lesion in C57BL/KsJ-db/db obese mice | Dietary supplement, 0.2% and 2.0% | Inhibited colonic premalignant lesion | [197] | ||
| HCT116 tumor xenograft in athymic nu/nu nude mice | Oral administration, 1 g/kg | Enhanced the efficacy of radiation therapy; suppressed NF-κB activity and expression | [198] | ||
| Colo205 and LoVo tumor xenografts in athymic nu/nu mice | Tail vein injection, 40 mg/kg | Inhibited tumor growth; suppressed angiogenesis | [199] | ||
| AOM-induced colon carcinogenesis in Il10−/− mice | Oral administration, 1% | Reduced colon tumors | [200] | ||
| AOM/DSS-induced colitis in C5757BL/6 mice | Oral administration, 25 mg/kg | Suppressed colitis-associated colon cancer and reduced tumor number | [201] | ||
| Cyanidin | Blackberries (Rubus fruticosus) |
ApcMin/+ mice | Dietary supplementation, 0.03%, 0.1% or 0.3% | Reduced adenoma counts | [202] |
| Daidzein | Soybeans and soy-based products, and nuts |
Male albino rats injected with DMH + DSS | Oral administration, 5 and 10 mg/kg | Reduced the level of CXCL1, AREG and MMP-9 | [193] |
| Delphinidin | Berries, pomegranates, eggplant, roselle, and wine | Male BALB/c nude mice xenograft with luciferase-transfected DLD-1 cells | Intraperitoneal injection, 100 μM | Suppressed integrin/FAK nexus; elevated miR-204–3p levels | [203] |
| Diosmetin | Chamomile, parsley, rosemary, rooibos tea, green tea, and other plants fof the mint and citrus family (Lamiaceae) |
NCr nu/nu nude mice injected with HCT-116 cells | Oral administration, 50 and 100 mg/kg | Downregulated Bcl-2; upregulated Bax | [204] |
| EGCG | Camellia sinensis L. Ktze | SW837 xenograft in male BALB/c nude mice | Oral administration, 0.01% and 0.1% | Reduced tumor growth; inhibited phosphorylation of VEGFR-2, Akt and ERK | [205] |
| AOM-induced colonic premalignant lesions C57BL/KsJ-db/db mice | Oral administration, 0.01% and 0.1% | Decreased p-IGF-IR, p-GSK-3β, β-catenin, COX-2 and cyclin D1 in colonic mucosa; reduced IGF-I, insulin, triglyceride, cholesterol and leptin in serum | [206] | ||
| AOM-induced colonic carcinogenesis in ICR mice | Oral administration, 0.25% and 0.5% | Inhibited large ACF formation; inhibited iNOS and COX-2 | [207] | ||
| HCT116-SDCSCs tumor xenograft in athymic nude mice | Cells were pretreated, 100 μM | Suppressed tumor formation; downregulated Notch1, Bmi1, Suz12, and Ezh1; upregulated miR-34a, miR-145 and miR-200c | [208] | ||
| DMH-induced colon carcinogenesis in Wister rats | Oral administration, 0.2% | Inhibited ACF and induced apoptosis | [209] | ||
| DMH-induced CRC in male Wistar rats | Oral administration, 50, 100 and 200 mg/kg | Lowered ACF formation; reduced tumor volume | [210] | ||
| Eriodictyol | Eriodictyon californicum | DMH-induced colon carcinogenesis in male albino Wistar rats | Intragastrical administration, 200 mg/kg | Suppressed the number of polyps, ACF and lipid peroxidation levels; upregulated catalase, SOD, GPX, GST, GSH and GR | [211] |
| Euxanthone | Polygala caudata | HT-29 cells induced tumor in BALB/c nude mice | Intraperitoneal injection, 20 and 40 mg/kg | Suppressed tumor growth; induced apoptosis; upregulated Bax; downregulated Bcl-2; induced caspase-3 cleavage; downregulated CIP2A expression and upregulated PP2A | [212] |
| Fisetin | Strawberry, apple, persimmon, grapes, onion, and cucumber | AOM and DSS induced CAC in male BALB/c mice | Oral administration, 20 mg/kg | Suppressed dysplastic lesions; induced apoptosis in colonic tissue; downregulated Bcl-2 and STAT3 | [213] |
| FC1 mice, 3K1 mice, ApcMin/+ males, 3K1ApcMin/+ mice, B6 congenic strain, B6 FC13K1ApcMin/+ mice | Intraperitoneal injection, 1 mg/animal | Upregulated AMPK phosphorylation; suppressed PI3K/Akt/mTOR signaling | [214] | ||
| Male athymic nude mice | Oral administration, 400 and 800 mg/kg | Induced apoptosis, caspase-8 and cyt.; inhibited IGF1R and Akt | [215] | ||
| CT-26 tumor in BALB/c nude mice | Subcutaneous injection, 5 mg/kg | Suppressed oncoprotein securin in p53-independent fashion | [216] | ||
| BALB/c mice | Tail vein injection, 50 mg/kg | Inhibited programmed cell death and angiogenesis | [217] | ||
| HCT116 tumor xenograft in mice NOD/Shi-scid-IL2R gamma (null) (NOG) | Intraperitoneal injection, 30, 60 and 120 mg/kg | Suppressed tumor growth in a dose-dependent manner | [218] | ||
| Flavone | Fruits and vegetables | DMM-induced colon carcinogenesis in C57BL/6J mice | Subcutaneous injection, 15 and 400 mg/kg | Suppressed ACF formation and multiplicity | [219] |
| Formononetin | Astragalus membranaceus | Female BALB/c-nu/nu mice injected with HCT-116 cells | Intraperitoneal injection, 20 mg/kg | Decreased VEGF, MMP-2 and MMP-9 levels | [220] |
| Furowanin A | Millettia pachycarpa Benth | HT-29 tumor xenograft in male athymic BALB/c nude mice | Intraperitoneal injection, 20 and 40 mg/kg | Suppressed tumor growth, induced apoptosis and autophagy; upregulated cleaved caspase-3, LC3BII, Beclin and p27; downregulated Ki-67, pSTAT3, Mcl-1, p62, and cyclin D | [221] |
| Genistein | Genista tinctoria | DMH-induced colon cancer in Wistar rats | Oral administration, 2.5 mg/kg | Regulated tumor microenvironment; upregulated SOD, CAT, GPx, GR, vitamin A, vitamin C, vitamin E and GSH; activated NRF2 and HO-1; reduced expression of CD133, CD44 and β-catenin | [222] |
| AOM-induced colon cancer in Sprague-Dawley rats | Dietary supplementation, 140 mg/kg | Suppressed the expression of cyclin-D1 and c-Myc; decreased expression of Wnt5a, Sfrp1, Sfrp2, and Sfrp5; downregulated Wnt/ β-catenin pathway | [223] | ||
| HCT116 tumor xenograft in athymic BALB/c mice | Oral administration, 75 mg/kg | Didn’t inhibit tumor growth; suppress metastasis; downregulated MMP-2 and EGFR3 | [224] | ||
| Genkwanin | Dried flower buds of Daphne genkwa | APCMin/+ mice | Oral administration, 12.5 and 25 mg/kg | Inducted host defense; reduced proinflammatory cytokine levels | [225] |
| AOM/DSS-induced C57BL/6J mice | Oral administration, 22.5 mg/kg | Suppressed colon cancer growth by triggering tumor cell death; inhibited of pro-inflammatory cytokines | [226] | ||
| Hesperidin | Citrus fruits | AOM-induced Swiss albino mice | Oral administration, 25 mg/kg | Inhibited NF-κB, iNOS and COX-2; reduced cellular oxidative indicators and improved antioxidant status | [227] |
| AOM-induced male Swiss albino mice | Oral administration, 25 mg/kg | Inhibited the constitutively active Aurora-A driven PI3K/Akt/GSK-3 and mTOR; activated autophagy | [228] | ||
| AOM-induced male F344 rats | Oral administration, 1000 ppm | Inhibited ACF formation; reduced colonic mucosal ODC activity and polyamine levels in the blood | [229] | ||
| DMH-induced CRC in albino rats | Oral administration, 25 mg/kg | Elevated the expression of Smad4 and activin A | [230] | ||
| Hinokiflavone | Selaginella tamariscina, Juniperus phoenicea, and Rhus succedanea | CT-26 tumor in female BALB/c mice | Intraperitoneal injection, 25 and 50 mg/kg | Suppressed tumor growth and proliferation; induced apoptosis; downregulated Ki-67 and MMP-9 | [231] |
| Icariside II | Epimedi Herba | SW620 tumor xenograft in nude BALB/c mice | Intraperitoneal injection, 25 mg/kg | Suppressed tumor growth; induced apoptosis | [232] |
| Icaritin | Epimedium sp. | HT-29 tumor xenograft in male nude mice | Oral gavage, 10 mg/kg | Suppressed tumor growth and volume | [233] |
| Isoangustone A | Glycyrrhiza sp. | SW480 tumor xenograft in male BALB/c nu/nu mice | Intraperitoneal injection, 10 mg/kg | Suppressed tumor growth; induced autophagic cell death; upregulated phosphorylation of AMPK, ACC and LC3B-1 and II levels | [234] |
| Isoliquiritigenin | Glycyrrhiza glabra | AOM/DSS-induced colon carcinogenesis in male BALB/c mice | Intragastrical administration, 3, 15 and 75 mg/kg | Suppressed tumorigenesis; inhibited macrophage polarization; upregulated TNF-α, INF-γ and IL-12; downregulated TGF-β, IL-10 and IL-1 and COX-2 | [235] |
| Glycyrrhiza uralensis Fisher | AOM-treated colon carcinogenesis in 344 rats | Oral administration, 100 ppm dietary supplementation | Suppressed ACF formation; induced apoptosis | [236] | |
| Isorhamnetin | Opuntia ficus-indica | HT-29 RFP xenograft in immunosuppressed mice | Oral administration, dose not reported | Elevated cleaved caspase-9, Hdac11, and Bai1 proteins | [237] |
| FVB/N mice treated with AOM/DSS | Oral administration, dietary supplement, dose not reported | Inhibited nuclear translocation of β-catenin and c-Src stimulation; activated CSK | [238] | ||
| Kaempferol | Apple, tea, broccoli, and grapefruit | DMH-induced colorectal carcinogenesis in male Wistar rats | Oral administration, 200 mg/kg | Restored CAT, SOD, and GPx | [239] |
| DMH-induced colon carcinoma in male Sprague Dawley rats | Oral administration, 200 mg/kg | Reduced multiple plaque lesions and preneoplastic lesions | [240] | ||
| DMH-induced colitis in Sprague-Dawley albino rats | Oral administration, 200 mg/kg | Reduced multiplicity of the ACF; downregulated COX-2 and PCNA | [241] | ||
| Luteolin | Celery, parsley, broccoli, onion leaves, carrots, peppers, cabbages, and tea | DMH-induced carcinogenesis in male Wistar rats | Subcutaneous injection, 0.2 mg/kg | Reduced the number of tumor polyps and colon polyploids; decreased COX-2 level in blood and colonic tissue | [242] |
| AOM-induced CRC in male BALB/c mice | Oral administration, 1.2 mg/kg | Reduced the levels of alkaline phosphatase and lactate dehydrogenase; suppressed iNOS and COX-2 | [243] | ||
| AOM-induced CRC in male BALB/c mice | Oral administration, 1.2 mg/kg | Reduced cytochrome b5, cytochrome P450 and cytochrome b5; enhanced the expression of UDP-GT and GST in colonic tissue; upregulated Nrf2 | [244] | ||
| CT-26 mediated lung metastasis | Oral administration, 10 and 50 mg/kg | Suppressed lung nodules and nodule volume; inhibited MMP-9 expression | [245] | ||
| AOM-induced colon carcinogenesis in BALB/c mice | Oral administration, 1.2 mg/kg | Inhibited MMP-2 and MMP-9; downregulated γ-glutamyl transferase, 5′ nucleotidase, cathepsin D, and carcinoembryonic antigen | [246] | ||
| HT-29 tumor xenograft in BALB/c nude mice | Intragastric administration, 100 mg/kg | Suppressed CRC metastasis; upregulated miR-384; downregulated pleiotrophin expression | [247] | ||
| HT-29 tumor xenograft in BALB/c nude mice | Intraperitoneal injection, 50 mg/kg | Inhibited tumor growth; induced apoptosis | [248] | ||
| Lysionotin | Lysionotus pauciflorus Maxim | HCT116 tumor xenograft in athymic nude mice | Intraperitoneal injection, 20 mg/kg | Suppressed tumor growth; induced ferroptosis | [249] |
| Magnolin | Magnolia biondii | HCT116 tumor xenograft in female BALB/c athymic nude mice | Intraperitoneal injection, 20 mg/kg | Suppressed tumor growth; downregulated LIF, STAT3 and Mcl-1 | [250] |
| Morin | Old fustic (Chlorophora tinctoria) and osage orange (Maclura pomifera) |
Male athymic nude mice injected with HCT-116 cells | Intraperitoneal injection, 30 and 60 mg/kg | Inactivated NF-κB signaling | [251] |
| Male albino Wistar rats injected with DMH | Intraperitoneal injection, 30 and 60 mg/kg | Modulated tumor metabolism via β-cateinin/c-myc signaling, glycolysis and glutaminolysis pathways | [252] | ||
| Pirc rats (F344/NTac-Apc am1137) | Dietary supplementation, 50 mg/kg | Restored the sensitivity to apoptosis by inhibiting LMW-PTP | [253] | ||
| Male albino Wistar rats injected with DMH | Intragastric administration, 50 mg/kg | Reduced ACF formation; suppressed fecal and mucosal biotransformation enzymes | [254] | ||
| Male albino Wistar rats injected with DMH | Intragastric administration, 50 mg/kg | Inhibited NF-κB and inflammatory mediators; suppressed proapoptotic pathway | [255] | ||
| DMH-induced colon carcinogenesis in a male Wistar rats | Oral administration, 50 mg/kg | Reduced lipid hydroperoxides and CD; increased superoxide SOD, CAT, GST, GPx, GR; decreased GSH | [256] | ||
| Myricetin | Tea, barriers, fruits, vegetables | DMH-induced rat colon carcinogenesis | Dietary supplementation, 50, 100 and 200 mg/kg myricetin | Restored CAT, GPx and GSH | [257] |
| APCMin/+ C57BL/6J mice | Oral gavage, 100 mg/kg | Promoted apoptosis in adenomatous polyps; lowered IL-6 and PGE2; downregulated p38 MAPK/Akt/mTOR signaling pathway | [258] | ||
| AOM/DSS-induced in BALB/c mice | Oral gavage, 40 and 100 mg/kg | Inhibited the development of colorectal tumors and colorectal polyps; decreased the levels of TNF-, IL-1, IL-6, NF-κB, p-NF-κB, COX-2, PCNA, and cyclin D1 | [259] | ||
| AOM/DSS-induced colitis in C57BL/6 mice | Oral administration, 100 mg/kg | Decreased CSF/M-CSF, IL-6, and TNF-α in colonic mucosa; inhibited NF-κB/IL-6/STAT3 pathway | [260] | ||
| Naringenin | Oranges, lemons, and grapefruit | AOM-induced colon carcinogenesis in rats | Dietary supplement, 0.02% | Reduce the number of HMACF by 51% and the proliferative index by 32% | [261] |
| DSS-induced murine colitis model | Oral administration, 50 mg/kg | Decreased iNOS, ICAM-1, MCP-1, COX-2, TNF-α, and IL-6 transcript levels | [262] | ||
| HT-29 tumor xenograft in athymic NIH Swiss nude mice | Oral administration, 40 mg/kg | Suppressed tumor growth; inhibited COX-1 | [263] | ||
| Naringin | Oranges, lemons, and grapefruit | DMH-induced female Wistar rats | Oral gavage, 10, 100, 200 mg/kg | Reduced cell proliferation and tissue iron levels; upregulated antioxidant mineral levels | [264] |
| AOM/DSS-induce Male C57BL/6 mice | Oral gavage, 50 and 100 mg/kg | Suppressed ER stress-induced autophagy in colorectal mucosal cells | [265] | ||
| AOM-induced ACF in Sprague Dawley rats | Oral administration, 200 mg/kg | Reduced total number of ACF; suppressed proliferation; induced apoptosis; downregulated COX-2 and iNOS | [266] | ||
| Nobiletin | Peel of various Citrus fruits | AOM-DSS-induced colon carcinogenesis in male CD-1 mice | Oral, dietary supplement, 100 ppm | Reduced tumor incidences and multiplicity | [267] |
| Orientin | Ocimum sanctum | DMH-induced CRC in male Wister rats | Intraperitoneal injection, 10 mg/kg | Reduced NF-κB, TNF-α and IL-6; downregulated Ki-67 and PCNA; suppressed iNOS and COX-2 | [268] |
| DMH-induced CRC in male Wister rats | Intraperitoneal injection, 10 mg/kg | Suppressed ACF and crypt multiplicity; elevated the level of antioxidants; downregulated phase I enzymes and upregulated phase II enzymes | [269] | ||
| Oroxylin A | Scutellaria baicalensis | AOM-DSS induced CRC in C57BL/6 mice | Dietary supplementation, 50, 100 and 200 mg/kg | Suppressed tumor formation and colitis associated CRC; induced apoptosis; downregulated IL-6, IL-1β, p-STAT3, cyclin D, and Bcl-2; upregulated Bax | [270] |
| HCT116 tumor xenograft in male athymic BALB/c nude mice and AOM-DSS induced colon carcinogenesis in male C57BL/6 mice | Oral administration, 150 and 300 mg/kg | Suppressed carcinogenesis and primary colon cancer progression; reduced triglyceride; downregulated HIF1α, Srebp1, FASN, ADRP and FABP7; upregulated CPT1 | [271] | ||
| Pectolinarigenin | Cirsium chanroenicum | Murine CT26 CRC cells were introduced into BALB/C mice | Intraperitoneal injection, 25 and 50 mg/kg | Induced apoptotic death of cancer cells; suppression STAT3 | [272] |
| Peonidin | Sweet potato (Ipomoea batatas) | AOM-induced CF-1 mice | Dietary supplementation, 10 to 30% | Blocked cell cycle at the G1 phase; activated caspase-3 | [273] |
| Petunidin | Lycium ruthenicum | Nude mice | Intraperitoneal injection, 25 and 50 mg/kg | Induced ferroptosis via inhibiting SLC7A11 | [274] |
| Phloretin | Manchurian apricot | COLO 205 cells derived tumor in BALB/c nude mice | Route of administration not reported, 25 mg/kg | Inhibited tumor growth; upregulated p53, p21 and E-cadherin | [275] |
| Polyphenon E | AOM-induced colon carcinogenesis in F344 rats | Oral administration, 0.24% | Induced apoptosis; decreased eicosanoid, prostaglandin E2, and interleukin B4 in plasma; decreased nuclear β-catenin and increased expression of RXRα,β and γ in adenocarcinomas | [276] | |
| Procyanidin | Cider apple (Malus domestica) | AOM-induced Wistar rats | Oral administration, 0.01% | Suppressed protein kinase; down-regulated of polyamine production; stimulated caspase-3 | [277] |
| Male C57/BL6 mice transfected with CT26 cells | Oral gavage, 30 mg/kg | Reduced cellular oxidative stress through modulation of Nrf2/ARE signaling | [278] | ||
| Quercetin | Apples, nuts, cauliflower, cabbage, onions, grapes, berries, broccoli, citrus fruits, cherries, green tea, and coffee |
AOM-induced colon tumor in C57BL/6J male mice | Dietary supplementation, 0.5% | Induced apoptosis; upregulated CB1-R; downregulated STAT3 and p-STAT3; downregulated Bax/Bcl-2 ratio | [279] |
| Subcutaneous DLD-1 human colon tumor fragment implant in male athymic nu/nu mice | Intraperitoneal injection, 30 mg/kg | Enhanced radiosensitivity by inhibiting ATM-mediated signaling pathway | [280] | ||
| AOM-induced CRC in male weanling Sprague-Dawley rats | Dietary supplement, 4.5 g/kg | Reduced the number of crypts; inhibited proliferation; induced apoptosis; suppressed COX-1, COX-2 and iNOS | [281] | ||
| AOM/DSS induced colon carcinogenesis in C57BL/6J mice | Dietary supplementation, 30 mg/kg | Reduced number and size of colon tumors; suppressed inflammation; downregulated LOP, NO, SOD, G6PD, and GSH | [282] | ||
| CT-26 lung tumor metastasis in BALB/c mice | Intraperitoneal injection, 50 mg/kg | Suppressed lung metastasis; induced apoptosis | [283] | ||
| HT-29 tumor xenograft in BALB/c nude mice | Subcutaneous injection, 10 mg/kg | Enhanced radiosensitivity; inhibited Notch-1 signaling | [284] | ||
| Rutin | Buckwheat, Mez, Labisia pumila, Sophora japonica L., Schum, Canna indica L., and Ruta graveolens L. | SW480 cell-induced tumor xenograft | Intraperitoneal injection, 20 mg/kg | Suppressed tumor growth; decreased angiogenesis and VEGF levels | [285] |
| Scutellarin | Scutellaria barbata | AOM/DSS-induced male C57BL/6 mice | Intraperitoneal injection, 25, 50 and 100 mg/kg | Inhibited Wnt/β-catenin signal transduction | [286] |
| RKO cells were subcutaneously implanted into female nude mice | Intraperitoneal injection, 50, 150 and 300 mg/kg | Suppressed tumor growth and metastasis | [287] | ||
| AOM/DSS-induced mice | Intraperitoneal injection, 25, 50 and 100 mg/kg | Suppressed the Hedgehog signaling cascade | [288] | ||
| Silibinin | Silybum marianum | LoVo cell deposition on eight days old fertilized chicken egg | Route of administration not reported, 9.64 μg/mL | Decreased in VDI; upregulated Flt-1 gene | [289] |
| AOM-induced CRC in male Wistar rats | Intragastric intonation, 300 mg/kg | Suppressed preneoplastic lesion formation; activated apoptosis; registered sub G0/G1 cell cycle arrest; reduced MMP-7, IL-1β and TNF-α | [290] | ||
| Tangeretin | Peel of citrus fruits | HT-29 induced tumor xenograft in BALB/c nude mice | Route of administration not reported, 5 mg/kg |
Suppressed tumor growth | [291] |
| Taxifolin | Olive oil, grapes, citrus fruits, and onion | HCT116 tumor xenograft in athymic male nude mice | Intraperitoneal injection, 15 and 25 mg/kg | Suppressed tumor growth; induced apoptosis; inhibited cyclin D; degraded β-catenin; inhibited of Akt phosphorylation | [292] |
| Tricin | Rice bran, oats, barley, and wheat | Colon26-Luc colon tumor and lung metastasis model in BALB/c mice | Oral gavage, 19 and 37.5 mg/kg | Suppressed tumor growth; reduced metastasis incidence | [293] |
| AOM-DSS induced CRC in male Crj: CD-1 mice | Dietary supplement, 50 and 250 ppm | Restored colonic length; reduced number of incidences and multiplicity of adenomas and adenocarcinomas; downregulated PCNA and TNF-α | [294] | ||
| Troxerutin | Tea and coffee | DMH-induced colon carcinogenesis in male albino Wistar rats | Oral administration, 12.5, 25 and 50 mg/kg | Lowered ACF formation and crypt multiplicity; reduced cytochrome P450, cytochrome b5, cytochrome P4502E1, NADPH-cytochrome P450 reductase, and NADH-cytochrome b5 reductase and upregulates phase GST, DTD and UDPGT | [295] |
| Vitexin | Passionflower, bamboo leaves, pearl, and millet | HCT116 tumor xenograft in nude BALB/c mice | Oral administration, 25, 50 and 100 mg/kg | Suppressed tumor growth; increased phosphorylation of JNK; upregulated LC3 II and ApoL1 | [296] |
| HCT116DR tumor xenograft in female athymic BALB/c nude mice | Oral administration, 25 and 50 mg/kg | Suppressed tumor growth; induced apoptosis; downregulated HSP90, HSP70, HSP27, Atg7, Beclin-1, LC3 II and Bcl-2; upregulated Bax and PARP1; cleaved caspase-3 and caspase-9 | [297] | ||
| Wogonin | Scutellaria baicalensis, Scutellaria radix | AOM/DSS-induced colitis related colon cancer in C57BL/6 mice | Gastric intubation, 60 mg/kg | Decreased cell proliferation; lowered the expression and secretion of IL-6 and IL-1β and expression of NF-κB; increased Nrf2 nuclear translocation | [298] |
| AOM-DSS-induced CRC animal model in C57BL/6 mice | Route of administration not reported, 50 and 100 mg/kg | Reduced tumor multiplicity; reverted colon length to normal | [299] | ||
| SW480 induced tumor xenograft in BALB/c nude mice | Intraperitoneal injection, 2 mM | Downregulated of YAP-1 and IRF3; upregulated p-YAP | [300] | ||
| Xanthohumol | Humulus lupulus | AOM-induced colorectal carcinogenesis in male Sprague-Dawley rats | Oral gavage, 5 mg/kg | Suppressed tumor growth; induced apoptosis; suppressed COX-2 and iNOS | [301] |
| Zapotin | Tropical fruit zapote blanco (Casimiroa edulis) | AOM/DSS-induced female CF-1 mice | Intragastric administration, 5 and 10 mg/kg | Induced cell cycle arrest and apoptosis |
[302] |
| Phenolic acids | |||||
| Caffeic acid | Coffee, wine tea | CT-26 lung metastasis in BALB/c mice | Oral administration, 0.1 and 0.5 g/kg | Inhibited lung metastasis; suppressed MEK1, TOPK, and TAP-induced activation of AP1, NF-κB and ERK signaling; inhibited TAP, EGF and H-Ras induced neoplastic transformation | [303] |
| HCT116 tumor xenograft in NSG mice | Intraperitoneal injection, 10 mg/kg | Inhibited CSC growth and self-renewal by inhibition of PI3K/Akt signaling | [304] | ||
| HCT116 tumor xenograft in BALB/c AnN Foxn-1 nude mice | Oral administration, 50 nmol/kg | Inhibited PI3K/Akt/mTOR pathway; suppressed MMP-9, cyclin D1, Cdk4, cyclin E, PCNA, FASN c-Myc, and N-cadherin expression; upregulated p21 | [305] | ||
| HT-29 tumor xenograft in BALB/c nude mice | Intragastric administration, CAPE (10 mg/kg); CAPE-pNO2 5, (10 and 20 mg/kg) | Inhibited tumor growth and VEGF expression; upregulated p53, p27, p21, cyt. c, and cleaved caspase-3; downregulated procaspase-3, Cdk2, and c-Myc; | [306] | ||
| HCT116 tumor xenograft in nude mice | Oral administration, 0.2 and 2 mg/kg | Suppressed tumor growth; displayed cell cycle arrest in S phase and autophagic cell death | [307] | ||
| Chlorogenic acid | Apple, betel, coffee beans, kiwi, grapes, eggplant, pear, plum, potato, and tea | MAM acetate-induced carcinogenesis hamsters | Oral administration, 0.025% dietary supplement | Reduced colon tumor incidences; registered antioxidative effect; inhibited the activity of microsomal enzyme | [308] |
| AOM-induced ACF in colon of male F344 rats | Oral administration, 0.025% dietary supplement | Reduced ACF formation and growth | [309] | ||
| Ellagic acid | AOM-induced colon tumors in rats | Oral administration, 250, 2500 and 5000 ppm | Inhibited the incidence of adenocarcinomas in the small intestine | [310] | |
| DMH-induced colon cancer in rats | Oral administration, 60 mg/kg | Lowered the frequency of ACF and lipid peroxidation; increased the activity of CAT, SOD, GPx, GR and GST; restored the levels of vitamin C, vitamin E and GSH | [311] | ||
| DMH-induced colon cancer in Wistar albino rats | Oral administration, 60 mg/kg | Inhibited NF-κB, iNOS, COX-2, TNF-α and IL-6; restored the levels 5′-ND, γ-GT, CEA, AFP and LDH | [312] | ||
| DMH-induced colon cancer in rats | Oral administration, 60 mg/kg | Inhibited PI3K-p58 activation; downregulated Akt and Bcl-2; upregulated Bax | [313] | ||
| DMH-induced colorectal cancer in rats | Oral administration, 60 mg/kg | Inhibited ACF formation; increased the activity of CAT, SOD, GPx, and GR; inhibited ODC expression through inhibition of c-MYC | [314] | ||
| DMH-induced colon cancer in male Laca mice | Oral administration, 10 mg/kg | Restored colon membrane alterations | [315] | ||
| Ferulic acid | Rice, wheat, pineapple, grains, and peanuts | AOM-induced colon cancer in male Fischer 344 rats | Oral administration, 250 ppm and 500 ppm | Reduced number and size of adenomas; increased the activity of GST and QR | [316] |
| AOM-induced colon carcinogenesis in F344 rats | Dietary supplement of 3-(4′-geranyloxy-3-methoxyphenyl)-2propenoate (geranylated derivative of ferulic acid) 0.1% and 0.2% | Decreased the number of ACF | [317] | ||
| Gallic acid | Barriers and pomegranates | DMH-induced colon cancer in male Wister rats | Oral administration, 50 mg/kg | Reduced lipid peroxidation, LOOH, CD, SOD, CAT, GSH, GR and GPx; reduced ascorbic acid and tocopherol levels | [318] |
| SW480 induced tumor xenograft in NOD SCID gamma NSG mice | Intraperitoneal injection, 200 mg/kg | Exerted antitumor activity mediated by interaction with G-quadruplexes | [319] | ||
| DSS-induced acute colitis in C57BL/6 mice | Oral administration, 5 and 25 mg/kg | Suppressed acute colitis; inhibited phosphorylation of STAT3 | [320] | ||
| HCT116 and HT-29 tumor xenografts in BALB/c nude mice | Intraperitoneal injection, 80 mg/kg | Suppressed p-SRC, p-EGFR, p-Akt and p-STAT3 | [321] | ||
| Ulcerative colitis in rats | Oral administration, 10 mg/kg | Suppressed colon cancer; induced ferroptosis | [322] | ||
| DMH-induced colon cancer in male albino Wister rats | Oral administration, 50 mg/kg | Elevated the activity of cytochrome P450, cytochrome b5, GST, DT-diaphorase and γ-GT | [323] | ||
| Geraniin | Phyllanthus amarus | SW480 tumor xenograft in nude mice | Oral administration, 10, 20 and 40 mg/kg | Suppressed tumor growth; induced apoptosis; inhibited phosphorylation of PI3K and Akt | [324] |
| p-Coumaric acid | Mushrooms, apples, pears, barriers, oranges, and beans | DMH-induced colon carcinogenesis in male albino Wistar rats | Intragastric intubation, 100 mg/kg | Reduced ACF, DACF, MDF and BCAC | [325] |
| Syringic acid | Olives, dates, pumpkins, grapes, and palms | DSS-induced mice | Oral administration, 25 mg/kg | Decreased the level of iNOS, COX-2, TNF-α, IL-1β and IL-6; reduced activation and accumulation of p-STAT-3 by decreasing expression of p65-NF-κB | [326] |
| DMH-induced colorectal cancer in male rats | Oral administration, 50 mg/kg | Reduced tumor incidences, tumor volume and average number of tumors | [327] | ||
| Lignans | |||||
| Arctigenin | Arctium lappa, Forsythia suspensa. | CT-26 cells derived lung metastasis model in BALB/c mice | Oral gavage, 50 mg/kg | Reduced the number of lung nodules; induced apoptosis in lung tissue; inhibited EMT in lung tissue; induced cleavage of caspase-3, caspase-9, and PARP; downregulated Bcl-2 and Bcl-xL; upregulated Bax | [328] |
| Daurinol | Haplophyllum dauricum | HCT116 tumor xenograft in athymic BALB/c (Slc/nu) nude mice | Oral administration, 5 and 10 mg/kg | Suppressed tumor growth; upregulated p-Chk1(Ser345)/Chk1 | [329] |
| Dehydrodiisoeugenol | Myristica fragrans Houtt | HCT116, zsw480, and patient-derived xenograft in female NOD/SCID mice | Intraperitoneal injection, 40 mg/kg | Suppressed tumor growth by inducing ER stress; upregulated BiP, PERK, and IRE1α | [330] |
| Gomisin A | Schisandra chinesis | CT-26 induced lung metastasis in female BALB/c mice | Intraperitoneal injection, 50 mg/kg | Suppressed lung metastasis; reduced the number of lung nodules; increased phosphorylation of AMPK and p38 in lung tissue | [331] |
| Honokiol | Magnolia grandiflora | SW620 tumor xenograft in female athymic BALB/c nude mice nu/nu | Intragastric administration, 50 mg/kg | Inhibited proliferation of CRC; upregulated TGF-β1 and p53 by upregulating BMP7 | [332] |
| Justicidin A | Justicia procumbens | HT-29 tumor xenograft in NOD-SCID mice | Oral administration, 6.2 mg/kg | Suppressed tumor growth; induced autophagy in tumor tissue; induced apoptosis | [333] |
| Magnolol | Magnolia officinalis | CT-26 and HT-29 tumor in BALB/c and Cg-Foxn1nu/CrlNarl nude mice respectively | Route of administration not reported, 50 and 100 mg/kg | Inhibited tumor growth; induced apoptosis; upregulation of Fas, Fas-L, cleaved caspase-3, cleaved caspase-9 and cleaved caspase-8; downregulated NF-κB, PKCδ, ERK, Akt, C-FLIP, and MCL-1; inhibition of PKCδ-NF-κB signaling | [334] |
| HCT116 tumor xenograft in female BLB/c nude mice | Intraperitoneal injection, 5 mg/kg | Suppressed tumor growth without showing any toxicity | [335] | ||
| Schisandrin B | Schisandra chinensis, Schisandra propinqua, and Schisandra rubriflora | AOM-DSS-induced CRC in C57BL/6 mice | Oral administration, 3.7–30 mg/kg | Suppressed SIRT1 | [336] |
| Secoisolariciresinol | Fitzroya cupressoides and Crossosoma bigelovii | HCT116 tumor xenograft in male BALB/c nude mice | Route of administration not reported, 50, 100 and 200 mg/kg | Inhibited tumor growth; induced pyroptosis; downregulated Ki-67; upregulated N-GSDMD | [337] |
| DSS-induced colitis in mice | Dietary supplementation, 200 mg/kg | Suppressed tumor growth; reduced IL-1β, IL-18, TNF-α and NLRP1 | [338] | ||
| Sesaminol | Sesamum indicum | Ethanol-induced CRC in male C57BL/6NCr mice | Oral administration, 2.5 mg/mice | Reduced colonic lesions; downregulated iNOS and CYP2E1; lowered TNF-α, IL-6, MCP-1 and NF-κB levels; increased cell adhesion by upregulation of ZO-1, occludin and cladulin-1 | [339] |
| Tracheloside | Carthamus tinctorious L. (safflower) | CT-26 lung metastasis in BALB/c mice | Oral administration, 25 and 50 mg/kg | Suppressed lung metastasis; induced apoptosis; upregulated E-cadherin RNA; downregulated N-cadherin, vimentin, snail and twist RNA | [340] |
| Vitexin | Vitex negudo | HCT116 tumor xenograft in female nu/nu mice | Intraperitoneal injection, 40 mg/kg | Inhibited tumor growth and lowered tumor volume; upregulated PUMA and p53; induced PUMA-mediated apoptosis | [341] |
| Stilbenes | |||||
| Piceatannol | Red and white grapes | AOM/DSS-induced colon tumor in C57BL/6J mice | Oral administration, 5 and 12.5 mg/kg | Decreased tumor number and size; decreased Ki-67- and COX-2-positive cell number; downregulated MCP1 and PD1 | [342] |
| Polydatin | Picea sitchensis | Caco-2 tumor xenograft in C57BL/6 mice | Subcutaneously into the tumor, 150 mg/kg | Suppressed tumor growth; upregulated miR-382; downregulated PD-L1 | [343] |
| Pterostilbene | Blueberries and cranberries | AOM-induced colonic ACF preneoplastic lesions and adenomas in male ICR mice | Oral administration, 50 or 250 ppm | Reduced ACF and adenoma formation; induced apoptosis; downregulated iNOS and COX-2; inhibited Wnt/β-catenin signaling through suppressing phosphorylation of GSK3β; inhibited VEGF, cyclin D, MMPs, Ras, PI3K/Akt and EGFR | [344] |
| AOM-induced colon tumors in F344 rats | Oral administration, 40 ppm | Reduced the proliferation of non-metastatic adenomas; downregulated IL-1β, IL-4, TNF-α, PCNA, β-catenin and cyclin D and p-NF-κB/p65 | [345] | ||
| AOM-induced colon tumor in male BALB/c mice | Oral administration, 50 or 250 ppm | Reduced NF-κB through inhibition of PKC-β phosphorylation; downregulated iNOS, COX-2 and aldose reductase; upregulated HO-1, GR and Nrf2 signaling | [346] | ||
| CL187 transplantation model in BALB/c nude mice | Intraperitoneal injection, 25, 50, 100 and 200 mg/kg | Inhibited Top1-mediated DNA damage repair pathway | [347] | ||
| AOM-induced colonic ACF preneoplastic lesions in F344 rats | Oral administration, 40 ppm | Inhibited ACF formation; blocked cell proliferation and iNOS | [348] | ||
| Resveratrol | Grapes, blueberries, raspberries, mulberries, and peanuts | LoVo cell-mediated metastasis model in mice | Intragastric administration, 50, 100 and 150 mg/kg | Inhibited metastasis; decreased tumor size; suppressed TGF-β1/Smad pathway; downregulated Snail and vimentin; upregulated E-cadherin expression | [349] |
| APCCKO/Krasmut mice | Dietary supplementation, 150 ppm and 300 ppm | Suppressed tumor formation; reduced tumor size; downregulated Kras expression | [350] | ||
| DSS-induced colon carcinogenesis in rats | Oral administration, 60 mg/kg | Reduced ACF and MDF | [351] | ||
| HCT116 tumor xenograft in ICR SCID mice | Oral administration, 150 mg/kg | Suppressed tumor growth; induced apoptosis; inhibited NF-κB |
[352] | ||
| COLO250-luc tumor xenograft in athymic mice | Injection in tumor, 6 μg/implant | Suppressed tumor growth | [353] | ||
| HT-29 tumor xenograft in BALB/c nu/nu mice | Intragastric administration, 480, 960 and 1920 mg/kg | Suppressed VEGF-mediated angiogenesis | [354] | ||
| Miscellaneous compounds | |||||
| Oleuropein | Olives (Olea europaea) | AOM-induced CRC in female A/J mice | Dietary supplementation, 125 mg/kg | Suppressed preneoplastic lesions; lowered tumor incidences; prevented DNA damage | [355] |
| Thymol | Thymus vulgaris L. | HCT116 tumor xenograft and lung metastasis model in BALB/c nude mice | Intraperitoneal injection, 75 and 150 mg/kg | Induced apoptosis; upregulated E-cadherin; downregulated N-cadherin; suppressed lung metastasis by inhibiting Wnt/β-catenin pathway | [356] |
| Verbascoside | Genus, Cistanche | HCT116 tumor xenograft in BALB/c nude mice | Tail vein injection, 20, 40, and 80 mg/kg | Upregulated HIPK2, p53 and Bax; downregulation Bcl-2 | [357] |
Abbreviation: ACC, acetyl CoA carboxylase; ACF, aberrant crypt foci; AFP, α-fetoprotein; AOM, azoxymethane; APC, adenomatous polyposis coli; BAX, B-cell lymphoma 2 associated x protein; BCAC, β-catenin accumulated crypts; BCL-2, B-cell lymphoma 2; BID, BH3 interacting-domain death agonist; CAC, colitis-associated colorectal cancer; CAT, catalase; CEA, carcinoembryonic antigen; CD, conjugated dienes; CIP2A, cancerous inhibitor of PP2A; c-MYC, cellular myelocytomatosis oncogene; COX-2, cyclooxygenase-2; CRC, colorectal cancer; CSK, C-terminal Src kinase; DACF, dysplastic aberrant crypt foci; DMH, 1,2-dimethylhydrazine; DNMT, DNA methyltransferase; EGCG, (-) epigallocatechin gallate; EGF-β, epidermal growth factor-β; EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase; FADD, Fas-associated protein with death domain; Flt-1, fms-like tyrosine kinase-1; GPx, glutathione peroxidase; GR, glutathione reductase; GSK-3β, glycogen synthase kinase-3β; GSH, glutathione; GST, glutathione S-transferase; γ-GT, γ-glutamyl transpeptidase; HMACF, high multiplicity aberrant crypt foci; IGF2, insulin like growth factor 2; IGFBP3, insulin like growth factor binding protein 3; IL-6, interleukin 6; iNOS, inducible nitric oxide synthase; KRAS, Kirsten rat sarcoma viral oncogene homolog; LC3b, light chain 3B of microtubule-associated proteins 1A/1B; LDH, lactate dehydrogenase; LMW-PTP, low molecular weight protein tyro-sine phosphatase; MAM, methyl azoxymethane; MAPK, mitogen-activated protein kinase; MDF, mucin-depleted foci; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; 5′-ND, 5′-nucleotidase; NEDD9, developmentally downregulated 9; NF-κβ, nuclear factor-κβ; Nrf-2, nuclear factor erythroid -2 related factor; ODC, ornithine decarboxylase; PCNA, proliferating cell nuclear antigen; PI3K, phosphoinositide 3-kinase; PP2A, protein phosphatase 2A; PTEN, phosphatase and TENsin homolog deleted on chromosome 10; QR, quinone reductase; SCID, severe combined immunodeficient; SIRT, Sirtuin 1; SOD, superoxide dismutase; STAT3, signal transducer and activator of transcription 3; TNF-α, tumor necrosis factor-α; Top1, topoisomerase 1; VDI, vascular density index; VEGF, vascular endothelial growth factor; γ-GT, γ-glutamyl transpeptidase.