Polyphenols in Colorectal Cancer: Current State of Knowledge including Clinical Trials and Molecular Mechanism of Action

Table 2

Important flavonols studied against CRC.

Name	Cell line/animal	Comments	Ref.
Quercetin	SW480 and HT-29	Inhibited cell growth and induced apoptosis via downregulation of ErbB2/ErbB3 signalling and the Akt pathway.	[101]
	Wistar rats	During DMH induced colon cancer assay, quercetin inhibited intestinal crypt cell proliferation in vivo, but the effect diminished as the level of dietary exposure increased.	[33]
	SW480	Inhibited β-catenin/TCF signalling.	[102]
	CACO-2 and HT-29	Had IC50 values in the range 30–40 µM.	[103]
	CO115 and HCT15	Produced synergistic effect in combination with 5-FU by increasing apoptosis via modulating p53.	[104]
	HT-29 xenografts in male nude mice	Induced apoptosis via AMPK activation and p53-dependent apoptotic cell death. Another study using HT29 cell line indicated that quercetin inhibited phosphorylation of EGFR and the ErbB2 receptor.	[105, 106]
	SW480	Antitumour action in SW480 colon cancer cells is related to the inhibition of expression of cyclin D1 and survivin through Wnt/β-catenin signalling pathway.	[107]
	HT-29	Resveratrol and quercetin in combination showed anticancer activity in colon cancer cells and repressed oncogenic microRNA-27a.	[108]
	HT-29 xenografts in female nude mice	Quercetin and trans-pterostilbene in combination facilitated elimination of colorectal cancer by chemoradiotherapy through a Bcl-2- and superoxide dismutase 2-dependent mechanism.	[109]
	CF1 mice, F344 rats, Wistar rats	Azoxymethane and dimethylhydrazine induced colon cancer study showed reduction of aberrant crypt foci and focal areas of dysplasia.	[110–115]
	mouse	Quercetin reduced polyp number and size distribution, which might be due to a reduction in macrophage infiltration.	[116]
Quercetin, myricetin, fisetin, galangin, chrysin, morin	LoVo and DLD-1	In LoVo cell lines the trend of IC50 values was fisetin < myricetin < quercetin < galangin < chrysin, whereas in DLD-1 cell line it was fisetin < myricetin < galangin < quercetin < chrysin. No significant antitumour effect was observed for Morin.	[75]
Quercetin, chrysin, kaempferol	SW480	Quercetin, chrysin, and kaempferol gave IC50 values of 85, 165, and 100 µM, respectively.	[80]
Myricetin	HCT-115, Colo-205	Myricetin induced cell death of human HCT-115 cells via Bax/Bcl2-dependent pathway. It inhibited matrix metalloproteinase 2 protein expression and enzyme activity in Colo-205 cells.	[117, 118]
Rutin	SW480, Nude mice	Rutin gave IC50 value of 125 µM and exerted in vivo antitumor and antiangiogenic activities.	[119]
	HT-29	Induced mitochondrial apoptosis through a caspase-dependent mechanism.	[120]
	CF1 –female mice	Inhibited azoxymethane-induced colonic neoplasia.	[113]
Chrysin	HT-29	Had IC50 value of 3.1 µM.	[121]
	HCT-116	Chrysin sensitized tumour necrosis factor-α-induced apoptosis in human tumor cells via suppression of nuclear factor-kappaB.	[122]
	HCT-116	Promoted tumour necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) induced apoptosis.	[123]
	SW480	Chrysin caused cell-cycle arrest at the G2/M phase in a dose-dependent manner.	[80]
	HCT116, DLD1 and SW837	Aryl hydrocarbon receptor was required for the chrysin induced apoptosis and the upregulation of TNF-α and -βgene expression and consequent activation of the TNF-mediated transcriptional pathway.	[124]
	Caco-2	Blocked topotecan-induced apoptosis in spite of inhibition of ABC-transporters.	[125]
Kaempferol	SW480	Sensitized TRAIL-induced apoptosis.	[126]
	HCT-116	The IC50 of kaempferol was 53.6 µM in HCT116 (p53+/+) cells and 112.7 µM in HCT116 (p53−/−) cells. It induced via ataxia-telangiectasia mutated-p53 pathway with the involvement of p53 up-regulated modulator of apoptosis.	[127]
	HT-29	Kaempferol increased chromatin condensation, DNA fragmentation, and the number of early apoptotic cells in a dose-dependent manner. Kaempferol increased the levels of cleaved caspase-9, caspase-3, and caspase-7 as well as those of cleaved poly (ADP-ribose) polymerase. Moreover, it increased mitochondrial membrane permeability and cytosolic cytochrome c concentrations.	[128]
Isorhamnetin	HT-29, FVB/N mice	Chemoprotective effects of isorhamnetin were linked to its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that were dependent on CSK expression.	[129]
	HCT-116, SW480 and HT-29	IC50 values for isorhamnetin in HCT-116, SW480, and HT-29 cell lines were 54.87, 56.24, and 43.85 µM, respectively. The mechanism of cell death was linked with PI3KAktmTOR pathway.	[130]
Fisetin	HT-29	Fisetin inhibited cyclin-dependent kinases leading to cell cycle arrest.	[131]
	HT-29	Enhanced radiosensitivity of p53-mutant HT-29 human colorectal cancer cells.	[132]
	HCT-116, HT-29	IC50 values for fisetin in HCT-116 and HT-29 cell lines were 132.2 and 57.7 µM after 72 h, respectively. The mechanism was induction of apoptosis by inhibition of COX2 and Wnt/EGFR/NF-kB-signalling pathways.	[133]
	HCT-116	Securin depletion sensitizes human colon cancer cells to fisetin-induced apoptosis.	[134]
Galangin	HCT-15, HT-29	Induced cell death via mitochondrial dysfunction and caspase-dependent pathway.	[135]
Morin	HCT-116	Had IC50 value less than 350 µg/mL after 48 h and induced apoptosis by modulation of Bcl-2 family members and Fas receptor.	[136]