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

Table 1

Important flavones studied against CRC.

Name	Cell line/animal	Comments	Ref.
Apigenin	SW480, HT-29, and Caco-2	Inhibited colon carcinoma cell growth by inducing a reversible G2/M arrest, associated with inhibited activity of p34cdc2 kinase, reduced accumulation of p34cdc2 and cyclin B1 proteins.	[63]
Apigenin	HCT-8	Suppressed tumour angiogenesis via HIF-1 and VEGF expression.	[64]
Apigenin	HCT-116, SW480, HT-29 and LoVo; mice	Cell death due to apoptosis is mediated by induction of proapoptotic proteins (NAG-1 and p53), cell cycle inhibitor (p21), and kinase pathways. In vivo data also supported in vitro results.	[65]
Apigenin	HT-29	Cytotoxic activity is related to cell cycle arrest through activation of caspase cascade and stimulation of apoptosis. Synergistic activity observed with 5-FU.	[66]
Apigenin	HT-29 and HRT-18	Inhibited metastasis by upregulating CD26 and degrades CXCL12 by increasing DPPIV activity.	[67]
Apigenin	Xenograft of SW480 cells in nude nice	Suppressed growth of colorectal cancer xenografts via phosphorylation and upregulated FADD expression.	[68]
Apigenin	SW480, DLD-1, and LS174T	Inhibited tumour growth and metastasis both in vitro and in vivo by upregulating TAGLN, downregulating MMP-9 expression, decreasing phosphorylation of Akt at Ser473 and in particular Thr308.	[69]
Apigenin	Xenograft study using DLD1, HCT-116, HT-29, HCT-8, and SW480	Synergistic effect was observed with ABT-263 and cell death is mediated via inhibition of Mcl-1, AKT, and ERK pathways.	[70]
Apigenin	HCT116	Induced cell death due to apoptosis and autophagy where apoptosis is via decreased expression of cyclin B1, Cdc2, and Cdc25c; increased expression of p53 and p21CIP1/WAF1; decreased levels of procaspase-8, -9, and -3.	[71]
	HT-29 and HCT-15	Oxidative stress resulted in senescence and chemotherapeutic effect.	[72]
	SW480 and HCT-15	Suppressed cell proliferation, migration, and invasion via inhibition of the Wnt/β-catenin signalling pathway.	[73]
	Sprague Dawley rats	Lowered the number of aberrant crypt foci (ACF) significantly.	[74]
Apigenin, luteolin, baicalein	LoVo and DLD-1	Apigenin had IC50 values in LoVo and DLD-1 cells lines at 44.7 µM and 29.6 µM, luteolin at 57.6 and 40.1 respectively. Baicalein has IC50 value 51.4 µM in DLD-1 cell line but no significant activity in LoVo cell lines.	[75]
Apigenin, luteolin, tangeretin, nobiletin	Colo 205	After 24-hour exposure, IC50 value for apigenin was greater than 100 µM. For luteolin, tangeretin, and nobiletin the values were 47.6 µM, 37.5 µM, and 66.2 µM, respectively.	[76]
Apigenin, baicalein, luteolin, tangeretin, diosmetin	HT-29 and Caco-2	IC50 values ranged from 49.4 µM to 203.6 µM in HT-29 cell lines and the trend was baicalein < tangeretin < luteolin < apigenin < diosmetin. For Caco-2 cell lines the trend was baicalein < tangeretin < luteolin < diosmetin < apigenin with values ranging from 56.4 µM to 1115.4 µM.	[77]
Luteolin	HT-29	Downregulated the activation of the PI3K/Akt and ERK1/2 pathways via reduction in IGF-IR signalling which may be one of the mechanisms responsible for the observed apoptosis and cell cycle arrest.	[78]
Luteolin	HT-29, SW480	In HT-29 cells, IC50 value was greater than 200 µM but in SW480 cells it is 90 µM.	[79, 80]
	Male Balb/c mice	Inhibited azoxymethane-induced colorectal cancer growth through activation of Nrf2 signalling; altered carbohydrate metabolizing enzymes; decreased expressions of iNOS and COX-2; restored reduced glutathione and protein thiols; decreased lysosomal enzymes, induced apoptosis by modulating Bcl2, Bax, and caspase-3; decreased mucin depleted foci, levels of glycoconjugates; controlled cell proliferation by inhibiting wnt/β-catenin/GSK-3β pathway. Luteolin also acts as antimetastatic agent by decreasing MMP-9 and MMP-2.	[81–88]
	HCT-15	Induced growth arrest by inhibiting wnt/β-catenin/GSK-3β signalling pathway, induces apoptosis by caspase-3 mediated manner.	[89]
	HT-29	Induced cell cycle arrest by inhibiting CDK2 and cyclin D1, induces apoptosis by activating caspase-3, -7, and -9.	[90]
	Wistar rats	Decreased the number and volume of 1,2-dimethyl hydrazine induced colon cancer and increased activities of enzymic and nonenzymic antioxidants.	[91, 92]
Pinocembrin	HCT-116, SW480	IC50 value in SW480 cell line was 50 µM and <100 µM in HCT-116 cell line. Pinocembrin triggers Bax-dependent mitochondrial apoptosis.	[93]
Tangeretin	HCT-116, HT-29	IC50 values were 22 µM and 26 µM, respectively.	[94]
	Colo 205	Induced cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating CDK inhibitors p21 and p27.	[76]
	LoVo and multidrug resistant LoVo/Dx	Greater activity was observed against resistant cells more than LoVo cells and gave synergistic effects with doxorubicin by increasing accumulation and sensitizing doxorubicin. It also induced caspase-3 activation and elevated surface phosphatidylserine exposure.	[95]
	HCT-116 and HT-29	In vitro and in vivo anticancer activity of tangeretin against colorectal cancer was enhanced by emulsion-based delivery system.	[96]
Vitexin-2-O-xyloside	LoVo and Caco-2	Showed IC50 values greater than 100 µg/mL in both cell lines but synergistically affected cell growth and apoptosis with raphasatin and (−)-epigallocatechin-3-gallate.	[97]
Nobiletin	F344 rats Sprague Dawley rats	Study on PhIp-induced cancer in F344 rats indicated that nobiletin did significantly reduce the total number of colonic aberrant crypt foci (ACF) compared to the control value.	[74, 98]
Baicalein, wogonin	HT-29 Xenograft assay in nude mouse	IC50 values for baicalein and wogonin after 48 h exposure were 100 µM and 150 µM, respectively. In vivo data supported the activity of baicalein but wogonin proved to be ineffective. Baicalein induced apoptosis in HT-29 cells via Akt inactivation and in a p53-dependent manner.	[99]
Baicalein	DLD-1 (mutant p53), SW48 (p53 wild-type), and HaCaT	Proteomic study proved that baicalein upregulated the expression of PRDX6, which attenuates the generation of ROS and inhibits the growth of CRC cells.	[100]