POLYPHENOLS AND NF-κB SIGNALING PATHWAY IN CANCER CELLS AND ACTIVATED MACROPHAGES

Among the different mechanisms by which polyphenols exert their anti-cancer effects, modulation of NF-κB activity is one of the most analyzed. In addition, due to the important role of tumor microenvironment inflammation in determining proliferation and survival of malignant cells, the effect of polyphenols on macrophages and cells involved in inflammation was analyzed (144). Indeed, the ability of several flavonoids to inhibit NF-κB activation in activated macrophages has been reported (145). The flavonoid apigenin has been demonstrated to have an inhibitory effect on NF-κB pathway in lipopolysaccharide (LPS)-stimulated mouse macrophages. In particular, apigenin regulated NF-κB activity by reducing phosphorylation of Ser⁵³⁶ in the p65 subunit and inactivating the IKK complex (146). The inhibitory effect on NF-κB activity is also displayed by quercetin in LPS-induced RAW 264.7 macrophages, in which the treatment with this flavonoid caused a significantly inhibition of NF-κB/p65 nuclear translocation (147). In addition, quercetin has also been demonstrated to inhibit NF-κB activation in the same cells through stabilization of the NF-κB/IκB complex and IκB degradation (148).

The impairment of NF-κB activity by EGCG has been investigated by Gupta et al. in human epidermoid carcinoma A431 cells. The authors demonstrated the inhibition of cell growth and the induction of caspases-dependent apoptosis in a dose dependent manner by EGCG (10-40 µg/ml). Moreover, EGCG induced a decrease in nuclear translocation of NF-κB/p65 (149).

The effects of some other polyphenols on NF-κB activation have been investigated by Romier et al. in human intestinal Caco-2 cancer cells. Among polyphenols, only chrysin and ellagic acid inhibited NF-κB activity, while others, such as genistein and resveratrol, determined a significant increase of NF-κB activation. The authors also reported that chrysin inhibited NF-κB activation by suppression of IκB-α phosphorylation (150).  

Garcia-Mediavilla et al. reported that flavones such as quercetin and kaempferol were able to inhibit NF-κB activation in human hepatocyte-derived Chang liver cells and to reduce cellular levels of phosphorylated IκB-α and IKKα proteins (151). Quercetin and genistein also inhibited the proliferation of MCF-7^ErbB2 breast cancer cells and induced apoptosis through down-regulation of IκB-α phosphorylation and subsequent suppression of the nuclear translocation of NFκB/p65 and its phosphorylation (152).

Different studies have shown that ACNs impair the transcriptional activity of NF-κB. Although the molecular mechanism through which ACNs interfere with NF-κB are not completely understood, it is without doubt that these compounds can prevent the degradation of the NF-κB inhibitor IκB by inhibiting the activity of the IκB kinase complex IKK. A study by Hafeez et al., reported that delphinidin was able to inhibit the growth of human prostate cancer cells (PC-3 cells and androgen refractory human PCa22Rν1 cells) with an IC50 value of 50-90 µM. Delphinidin (30-180 µM) also induced caspases-dependent apoptosis in the same cells in a dose-dependent manner, through the decrease of phosphorylation of IκB kinase γ (NEMO) and of NF-κB inhibitory protein IκB-α. Moreover, delphinidin reduced phospho-NF-κB/p50 at Ser529and phospho-NF-κB/p65 at Ser536 in the nuclear fraction, which led to inhibition of NF- κB/p65 DNA binding activity. Finally, the administration of delphinidin to mice carrying prostate cancer cell tumor xenografts induced a significant reduction of tumor growth and NF-κB protein levels in tumor tissues (153,154). Similar results were obtained by Yun et al. in human colon cancer cells. Delphinidin impaired cancer cell growth (IC₅₀: 110 μM) and induced apoptosis (at doses of 30 to 240 μM). Moreover, this polyphenol inhibited the activation of IKKα and IκB-α phosphorylation in a dose-dependent manner and the constitutive activation of NF-κB (155).

Ding et al. studied the inhibition of NF-κB by C3G derived from blackberries, in a mouse model of skin carcinogenesis. Pretreatment of mouse epidermal cells with C3G inhibited TPA- and UVB-induced NF-κB and AP-1 activity. In addition, C3G suppressed TPA- and UVB-induced phosphorylation of p38, ERK, JNK in a dose-dependent manner. These molecular events led to the suppression of tumor cell growth and metastasis in nude mice (156). Furthermore, other studies reported the inhibition of the LPS-induced phosphorylation of IκB-α and nuclear translocation of NF-κB by C3G and cyanidin in mouse leukemic macrophage-like cells (157), and by C3G in a human monocyte/macrophage cell line (158). In agreement with these results, Hecht et al. confirmed that C3G and its aglycon form, cyanidin chloride, derived from freeze-dried black raspberries, were good inhibitors of NF-κB activity induced by the mutagenic and highly carcinogenic benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) (159).

Wang et al. investigated the effects of ACNs from black raspberries on the development of N-nitrosomethylbenzylamine (NMBA)-induced rat esophagus tumors. They provided evidence that diets containing freeze-dried black raspberries suppressed the development of (NMBA)-induced tumors in the rat esophagus and this anti-tumor effect was associated with the reduction of expression of NF-κB/p50 and COX-2 at tumor level (160).

Pozo-Guisado et al. focused their study on the effect of resveratrol in MCF-7 human breast cancer cells. They observed that resveratrol (50-150 µM) induced a decrease in Bcl-2 protein levels and the subsequent activation of apoptosis in this cell line in a dose-dependent manner. Moreover, the authors found that the down-regulation of Bcl-2 expression levels was associated to the inhibition of NF-κB (161).

Table 1. Biological effects of polyphenols on ErbB receptors, MAPKs, HH/GLI and NF-кB signaling pathways

Signaling Pathways	Polyphenol	Biological effects	Ref.
ErbB receptors	EGCG	↓ ErbB2 phosphorylation and activation; ↓ PI3K/Akt, NF-κB ↓ ErbB2-ErbB3 phosphorylation; ↓ PI3K/Akt, MAPK ↓ EGFR, Stat3, Akt activity ↓ ErbB2 phosphorylation; ↓Stat3, c-fos, cyclin D1 ↓ Akt activity ↓ EGFR, ErbB2 phosphorylation ↓ EGFR, ErbB2, ErbB3 phosphorylation ↓ EGFR activation	(68) (69) (70) (71) (73) (75) (76) (77-79)
	EGCG + ERLOTINIB EGCG + GEFITINIB EGCG + DEXAMETHASONE EGCG + U0216	↓ EGFR, Akt, ERK1/2 phosphorylation ↓ EGFR phosphorylation; ↓phospho-ERK, -JNK, -p38, -Akt ↓ Akt, NF-κB ↓ MAPK	(80) (72) (74) (74)
	DELPHINIDIN	↓ EGFR, ErbB2 phosphorylation; ↓ ERK1/2 activity ↓ EGFR, Akt, ERK1/2, JNK1/2, p38 phosphorylation ↓EGFR, ErbB2 tyrosine kinase activity; ↓ ErbB3 phosphorylation ↓ ErbB2, ERK1/2, Akt phosphorylation	(82) (83) (84) (85)
	LIGNANS, SECORROIDS, GENISTEIN	↓ ErbB2 phosphorylation	(89,90,94,95)
	APIGENIN	↓ EGFR, ErbB2 phosphorylation	(12)
	LUTEOLIN	↓ EGFR phosphorylation; ↓ MAPK, PI3K/Akt activation	(87)
	QUERCETIN	↓ EGFR phosphorylation; ↓ ERK1/2 activity ↓ ErbB2 tyrosine kinase activity; ↓ PI3K/Akt phosphorylation	(82) (93)
	GENISTEIN + ERLOTINIB + GEFITINIB	↓ EGFR phosphorylation; ↓ Akt; ↓ NF-κB activation	(81)
	TANNIC ACID, ELLAGITANNINS, PROCYANIDINS	↓ EGFR phosphorylation	(88,91,92)
	LIGNANS AND SECORROIDS	↓ ErbB2 phosphorylation; ↓ Akt, MAPK, Stat3	(96)
	CURCUMIN	↓ ErbB2 tyrosine kinase activity ↓ EGFR phosphorylation; ↓ c-fos; ↓ ERK, MKK4, JNK activity ↓ EGFR, ERK1/2 phosphorylation ↓ Akt, MAPK phosphorylation ↓ ErbB2, phospho-Akt, phospho-MAPK, NF-кB ↓ ErbB2 ↓ EGFR, ErbB2 ↓ EGFR, phospho-ERK1/2 ↓ Akt, phospho-ERK	(97) (99) (100) (102) (103) (104) (110) (112) (16)
	CURCUMIN + EGCG CURCUMIN + RESVERATROL CURCUMIN + DESATINIB CURCUMIN + FOLFOX CURCUMIN + BETULINIC ACID CURCUMIN + β-PHENILETYLISOTHIOCYANATE	↓ EGFR, Akt ↓ EGFR, NF-κB ↓ EGFR, ErbB2, ErbB3; ↓ Akt, ERK phosphorylation; ↓ NF-κB ↓ EGFR, ErbB2, ErbB3; ↓ Akt phosphorylation ↓ EGFR; ↓ Akt phosphorylation ↓ EGFR phosphorylation; ↓ PI3K/Akt activation; ↓ NF-κB	(101) (105) (106) (107,108) (109) (113)
MAPKs	ANTHOCYANINS	↑ p38, ↓ Akt ↓ ERK1/2 phosphorylation; ↓ AP-1	(114) (115)
	APIGENIN	↑ JNK, ERK phosphorylation; ↓ p38, PI3K/Akt phosphorylation ↓ p38, MAPK, PKA, PI3K/Akt	(116,117) (118)
	FLAVANONE, 2’-OH FLAVANONE	↓ ERK1/2, p38 phosphorylation; ↓ AP-1, NF-κB activation	(119)
	QUERCETIN	↓ ERK1/2, Akt phosphorylation; ↓ NF-κB activation; ↑ AP-1, JNK ↓ Akt activation; ↑ ERK-MEK1/2 phosphorylation	(120,121) (122)
	GENISTEIN	↑ ERK, JNK phosphorylation	(116)
	KAEMPFEROL,  NARINGENIN	↑ ERK, JNK phosphorylation	(116)

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RESVERATROL

↑ MAPKs activation

↓ p38, Akt, cyclin D1, Pak1; ↑ phospho-ERK1/2

↓ Cyclin D1, MEK1, ERK1/2, c-Jun

(123)

(124)

(125)

RESVERATROL + BLACK TEA

↓ p38, JNK1/2, ERK1/2 activity

(126)

EGCG, THEAFLAVINS

↓ PI3K/Akt; ↑ ERK1/2

(127)

CURCUMIN

↓ ERK, Akt phosphorylation

↓ Akt; ↓ p38 activation

(128)

(129)

5,7-DIMETHOXY-COUMARIN

↓ MEK1/2 activity; ↓ ERK1/2 phosphorylation

(14,130)

HH/GLI

CURCUMIN

↓ SHH, GLI-1, PTCH1; ↓Akt, NF-κB

(132,136)

EGCG

↓ hIHH, PTCH1, GLI-1

↓ SMO, PTCH1, PTCH2, GLI-1, GLI-2

(134,136)

(142)

APIGENIN, BAICALEIN, QUERCETIN, RESVERATROL

↓GLI-1

(136)

GENISTEIN

↓ GLI-1

(136,139)

NF-κB

APIGENIN

↓ NF-κB phosphorylation; ↓ IKK activation

(146)

QUERCETIN

↓ NF- κB/p65 nuclear translocation

↓ NF- κB activation

(147)

(148)

EGCG

↓ NF- κB activity and nuclear translocation

(149)

QUERCETIN, GENISTEIN

↓ NF- κB nuclear translocation

(152)

CHRISIN, ELLAGIC ACID, QUERCETIN, KAEMPFEROL

↓ NF- κB activity

(150,151)

DELPHINIDIN

↓ IκB-γ, IκB-α phosphorylation; ↓ NF-κB/p65 DNA binding activity

↓ IKK-α activation; ↓ IκB-α phosphorylation; ↓ NF- κB activation

(153,154)

(155)

C3G

↓ NF- κB, AP-1 activity; ↑ p38, ERK, JNK phosphorylation

(156,159)

BLACK RASPBERRIES ANTHOCYANINS

↓ NF- κB/p50

(160)

RESVERATROL

↓ NF- κB, Bcl-2

(161)

CURCUMIN

↓ IκB-α phosphorylation and degradation; ↓ NF- κB activation; ↓ AP-1, COX-2

↓ NF- κB activation; IκB-α degradation; ↓ NF- κB nuclear translocation; ↓ ERK1/2

(162)

(163)

Curcumin was shown to modulate NF-κB activity as well. Dyvia et al. studied the effects of curcumin in human papillomavirus (HPV)-associated cervical cancer cells. Curcumin induced apoptosis in these cells and blocked IκB-α phosphorylation and degradation, leading to the inhibition of NF-κB activation. In addition, curcumin

down-regulated AP-1 and COX-2 (162). Chun et al. assessed the effects of curcumin on mouse skin tumorigenesis in vivo. In particular, the authors investigated the effects of this polyphenol on TPA-induced expression of NF-κB and COX-2 in female ICR mouse skin. Curcumin inhibited the expression of COX-2 protein and the activation of NF-κB in a dose-dependent manner. The inactivation of NF-κB was due to the inhibition of IκB-α degradation and the subsequent translocation of NF-κB/p65 into the nucleus. Furthermore, curcumin was also able to inhibit the catalytic activity of ERK1/2 in mouse skin (163).