Table 2.

Representative Flavonoids and their Underlying Anticancer Effects.

Flavonoid Subclass	Name of Flavonoid	Metabolites Produced by Gut Microbiota	Type of Cancer (s)	Targeted Pathways	Mechanism of Action	Methods of Testing	Model Used		References
							In Vivo	In Vitro
Flavonol	1. Rutin	Quercetin -3- O- glucoside Quercetin	Colorectal cancer Colonic adenocarcinoma	Reactive oxygen species (ROS) Apoptosis Angiogenesis	Inhibit tumor cell proliferation Impaired attachment of cells in dose-dependent matter (38 ± 1.9%) Inhibit cell migration Protect cells from inflammation, oxidative stress, and DNA damage	Cell viability assay Cell migration assay Adhesion assay Haptotaxis assay	Azoxymethane (AOM) treated mice	Caco-2 cells HT29 cells	[107,108,109]
	2. Fisetin	No available data	Gastric cancer Colorectal cancer	Apoptosis Caspase -7 B-cell lymphoma 2 (Bcl-2)	Reduce cellular proliferation significantly Reduce anti-apoptotic proteins Reduce the activation of extracellular- signal-regulated kinase ½ in dose- dependent matter Increase the proportion of cells at G2/M phase Increase the level of caspase 7 Induce cellular apoptosis (87% after treatment)	Flow cytometry Western blot Cell counting kit-8 assay Immunoblotting	Apc Min/+ males Wistar rats	SGC7901 cells PIK3CA cells	[110]
	3. Kaempferol	Kaempferol -3-O- glucoside p-coumaric acid kaempferol 3-(4 hydroxyphenyl) propionic acid 3-phenylpropionic acid	Gastric cancer Colorectal cancer	B-cell lymphoma 2 (Bcl-2) Protein kinase B (Akt) Cyclooxygenase-2	Inhibit cellular proliferation significantly Inhibit the growth of tumor xenograft Reduce the expression level of cyclin B, Cyclin-dependent kinase 1 and cdc25c phosphatase Reduce the expression of Bcl-2 Increase the proportion of cells at G2/M phase Increase the level of caspase 3 and 9 * Induce cellular apoptosis	Cell viability assay Western blot Tumor xenograft experiment Ki-67 immunochemistry	Mice	SGC7901 cells MKN28 cells	[111,112]
	4. Quercetin	3,4-dihydroxyphenylacetic acid 3-(3-hydroxyphenyl) propionic acid 3,4-dihydroxybenzoic 4-hydroxybenzoic acid	Gastric cancer	Nuclear factor kappa (NF-κB) Protein kinase B (Akt) AMP-activated protein kinase	Inhibit NF-κB, AMPKA pathways Reduce matrix metalloproteinases Reduce cellular migration and invasion Reduce tumor metastasis Induce cellular apoptosis	Cell viability assay Western blot Flow cytometry Quantitative reverse transcription PCR	Mice	AGS cells GCBGC823 cells MGC803 cells	[113,114]
	5. Isorhamnetin	3-O-neohesperidoside Isorhamnetin -3- glucoside Aglycone isorhamnetin	Gastric cancer Colorectal cancer	Protein kinase B (Akt) Phosphoinositide 3-kinase Peroxisome proliferator-activated receptor gamma (PPAR-γ)	Inhibit cellular proliferation Reduce the expression of anti-apoptotic proteins Reduce cellular invasion Induce cellular apoptosis Increase PPAR-γ expression	PPAR-γ competition assay Flow cytometry Western blot Invasion assay	Mice	AGS cells MKN45 cells	[115,116]
	6. Morin	Morin glucuronides Morin sulfates	Colorectal cancer	Peroxisome proliferator-activated receptor gamma (PPAR-γ) Nuclear factor kappa (NF-κB) B-cell lymphoma 2 (Bcl-2)	Inhibit cellular proliferation in dose and time dependent matter Inhibit NF-κB, AMPKA pathways Reduce glucose uptake Reduce antioxidant activities Reduce ATP production level Induce cellular apoptosis Increase PPAR-γ expression	Cell viability assay Flow cytometry Immunoblotting Antioxidant assay		SW480 cells	[117,118]
Flavanones	7. Hesperidin	Hesperetin	Gastric cancer	Mitochondrial pathway (increase ROS) B-cell lymphoma 2 (Bcl-2) Cytochrome c specificity protein 1 (Sp1) Phosphatase and tensin homolog	Inhibit cellular proliferation in dose and time dependent matter Inhibit xenograft tumor Reduce the expression of Bcl-2 Supress mRNA/protein level of Sp1 Reduce ATP production level Induce cellular apoptosis through PTEN expression Increase cytochrome c, caspase 3 and 9 expression	Cell viability assay Western blot Transwell invasion assay Antibody studies	Mice	SGC-7901cells MGC-803 cells HGC-27 cells	[119,120]
	8. Naringenin	Aglycone naringenin	Gastric cancer Colorectal cancer	B-cell lymphoma 2 (Bcl-2) Cyclin D1 protein Prostaglandin-endoperoxide synthase 2 (COX-2)	Inhibit cellular proliferation in dose and time dependent matter Reduce cellular migration and invasion Reduce the expression of Bcl-2 Reduce cyclin D1 protein Induce cellular apoptosis Increase the level of cleaved caspase	Quantitative reverse transcription PCR Western blot Proliferating cell nuclear antigen (PCNA)	Azoxymethane (AOM) treated rats Wistar rats	SGC-7901cells SW480 cells HCT-116 cells	[121,122]
	9. Eriodictyol	Eriocitrin	Colorectal cancer	β-glucuronidase Lipid peroxidation Superoxide dismutase (SOD) catalase (CAT)	Supress cellular proliferation Reduce lipid peroxidation levels Reduce aberrant crypt foci Reduce microbial enzymatic activities in feces Reduce Argyrophilic nucleolar organizer region (AgNOR) Induce cellular apoptosis Increase the level of cleaved caspase	AgNOR staining Bacterial enzymes assay Lipid peroxidation Histopathological assays	Albino wistar rats		[123]
Isoflavones	10. Genistein	Dihydrogenistein 6-hydroxy-O-desmethylangolensin 2-(4-hydroxyphenyl) propionic acid	Gastric cancer Colorectal cancer	Protein kinase B (Akt) Notch1 signaling E-cadherins Nuclear factor kappa (NF-κB)	Blocked high cell migration capacity of CD44 Reduce Glil and CD44 expression Supress cellular invasion and metastasis Decrease epithelial-mesenchymal transition (EMT) expression Inhibit Notch1 and NF-κB expression Induce cellular apoptosis Increase E-cadherins and caspase 3 expression	Colony formation assay Western blot Flow cytometry Real time polymerase chain reaction Immunofluorescence		MKN 45 cells HT-29 cells HCT-116 cells	[124,125]
	11. Daidzein	Dihydrodaidzein O-desmethylangolensin S- equol	Colorectal cancer Choriocarcinoma	Peroxisome proliferator-activated receptor gamma (PPAR-γ) Extracellular-signal-regulated kinase (P-ERK)	Reduce lipid droplet accumulation Reduce Phosphoinositide 3-kinase (PI3K) expression Inhibit cellular proliferation Reduce the expression of P-ERK Induce cellular apoptosis Induce m-RNA expression of PPAR-γ	Colony formation assay Western blot Flow cytometry Real time polymerase chain reaction Immunofluorescence	Nude mice	JAR cells JEG-3 cells HT-29 cells	[126]
Anthocyanins	12. Cyanidin	Cyanidin-3- glucoside	Gastric adenocarcinoma	Combined activity of bacteria and host enzymes	Reduce cellular proliferation Induce cellular apoptosis through caspase-3 activation	Cell viability assay High-performance liquid chromatography (HPLC)		AGS cells	[127]
	13. Delphinidin	Gallic acids	Colorectal cancer	αV/β3-integrin miR-204-3p	Inhibit colony formation Reduce cellular viability (not significant) Inhibit migration and invasion through αV/β3-integrin reduction and miR-204-3p enhancement	Colony formation assay Western blot Flow cytometry Microarray	BALB/C nude mice	SW480 cells SW620 cells	[128]
	14. Pelargonidin	4-hydroxybenzoic	Colorectal cancer	Apoptotic pathway	Reduce the expression of Bcl-2 Induce cellular apoptosis through intrinsic pathway Induce the loss of mitochondrial membrane potential	Cell viability assay Western blot		HT-29 cells	[129]
Flavones	15. Baicalein	Baicalein	Gastric cancer Colorectal cancer	Inhibitory cell cycle proteins E-cadherins epithelial-mesenchymal transition (EMT)	Supress cellular proliferation, migration and invasion in dose and time dependent matter Decrease the expression of EMT Induce cellular apoptosis Increase the expression of E- cadherins Increase the level of cell cycle inhibitory proteins (P53 and P21)	Flow cytometry Western blot Cell counting kit-8 assay Transwell assay Colony formation assay Real time polymerase chain reaction	Mice	SGC-7901cells SW480 cells HCT-116 cells HT-29 cells	[130,131]
	16. Luteolin	No available data	Gastric cancer Colorectal cancer	E-cadherins epithelial-mesenchymal transition (EMT) Protein kinase B (Akt) Mechanistic target of rapamycin (mTOR) Notch1 signaling	Reduce cellular viability in time and dose dependent matter Inhibit cellular proliferation, migration and invasion Reduce aberrant crypt foci Decrease the expression of EMT by increasing E-cadherins and decreasing Notch1 signaling Induce cellular apoptosis	Flow cytometry Western blot Cell viability assay Xenograft assay	Mice	SGC-7901cells MKN 45 cells BGC-832 cells	[132,133]
	17. Diosmin	Diosmetin	Colorectal cancer	No available data	Inhibit aberrant crypt foci Reduce cellular proliferation	Histopathological assays Microscopic evaluation	Azoxymethane (AOM) treated rats		[134]
	18. Apigenin	Apigenin 3-(4-hydroxyphenyl) propionic acid	Gastric cancer Colorectal cancer	β-catenin B-cell lymphoma 2 (Bcl-2)	Reduce mitochondrial membrane potential Inhibit cellular proliferation Reduce the expression of Bcl-2 Increase the expression of caspase 3 Induce cellular apoptosis through intrinsic and extrinsic pathways	Flow cytometry Western blot Cell viability assay Real time polymerase chain reaction		SGC-7901cells HCT-116 cells HGC-27 cells	[135,136]
	19. Tangeretin	Tangeretin-O-glucuronides	Gastric cancer	Notch1 signaling	Reduce cellular viability, invasion and migration Inhibit Notch1 signaling pathway Decrease the expression of EMT by increasing E-cadherins Increase caspase 3 and 9 expression Induce cellular apoptosis through intrinsic and extrinsic pathways	Flow cytometry Western blot Cell viability assay Microarray	Nude mice	AGS cells MKN-45 cells MGC 80-3 cells	[137,138]
	20. Wogonin	Wogonin	Gastric cancer Colorectal cancer	P53 translocation	Reduce tumor multiplicity Induce cellular apoptosis through increase endoplasmic reticulum stress	Flow cytometry Western blot Cell viability assay Real time polymerase chain reaction	Azoxymethane (AOM) treated mice	HCT-116 cells	[139,140]
	21. Chrysin		Gastric cancer Colorectal cancer	Nuclear factor kappa (NF-κB) SALL-4 Early growth response 1 (Egr1)	Reduce tumor volume by downregulating SALL-4 expression Reduce cellular proliferation Supress the expression of NF-κB and Egr1 Increase caspase 3 and 9 expression Induce cellular apoptosis through intrinsic pathway (caspase 3 and 9)	Flow cytometry Western blot Cell viability assay Quantitative reverse transcription PCR Apoptotic assays	BALB/mice	HT-29 cells CT-26 cells	[141]