Cancer Protective Role of Selected Dietary Polyphenols via Modulating Keap1/Nrf2/ARE and Interconnected Signaling Pathways

Figures & data

Table 1. Common dietary sources of the 21 selected polyphenols.

Name	Common Dietary Sources (Scientific Name)	References
Xanthohumol (1)	Hops (Humulus lupulus)	(57)
Punicalagin (2)	Pomegranates (Punica granatum)	(58,59)
Resveratrol (3)	Grapes and wine (Vitis vinifera); Peanuts (Arachis hypogaea); Soybean (Glycine max)	(60)
Methyleugenol (4)	Cloves (Syzygium aromaticum); Lemon grass (Cymbopogon spp.); Sweet basil (Ocimum basilicum); Nutmeg (Myristica fragrans)	(61–63)
6-Shogaol (5)	Ginger (Zingiber officinale)	(64)
Chlorogenic acid (6)	Robusta Coffee (Coffea canephora, Coffea arabica); Yerba Mate (Ilex paraguariensis); Winter’s Bark (Drimys winteri)	(65)
Ferulic acid (7)	Various fruits, grains and beverages as well as aubergines (Solanum melongena); Tomatoes (Solanum lycopersicum); Artichokes (Cynara cardunculus var. scolymus); Bamboo Shoots (Bambusa vulgaris)	(66)
Carnosic acid (8)	Rosemary (Rosmarinus officinalis)	(67)
Carnosol (9)	Rosemary (Rosmarinus officinalis); Mountain desert sage (Salvia pachyphylla)	(68)
Ellagic acid (10)	Cranberries (Vaccinium macrocarpon); Raspberries (Rubus idaeus); Walnuts (Juglans regia); Pecan nuts (Carya illinoinensis)	(69)
Apigenin (11)	Parsley (Petroselinum crispum); Celery (Apium graveolens); Chamomile tea (Matricaria chamomilla)	(70)
Catechin (12)	Green/White/Black tea (Camellia sinensis)	(71,72)
Epicatechin (13)	Green tea (Camellia sinensis); Grapes (Vitis vinifera); Cocoa (Theobroma cacao)	(73,74)
EGCG (14)	Green tea (Camellia sinensis)	(75)
Fisetin (15)	Strawberries (Fragaria × ananassa); Persimmon (Diospyros kaki); Grapes (Vitis vinifera); Apples (Malus spp.); Cucumber (Cucumis sativus)	(76)
Genistein (16)	Soybean seeds (Glycine max)	(77)
Isoorientin (17)	Bamboo (Phyllostachys pubescens, Sasamorpha borealis); Buckwheat (Fagopyrum esculentum) Foxtail lilies shoots (Eremurus spectabilis)	(78,79)
Quercetin (18)	Red wine, medicinal herbs, and Onion (Allium cepa); Blueberries (Vaccinium sect. Cyanococcus); Green tea (Camellia sinensis)	(80)
Luteolin (19)	Various medicinal herbs, and Celery (Apium graveolen); Green Peppers (Capsicum annuum); Parsley (Petroselinum crispum); Perilla leaves (Perilla frutescens); Chamomile tea (Matricaria chamomilla)	(81)
Rutin (20)	Asparagus (Asparagus officinalis); Buckwheat (Fagopyrum esculentum); Cherries (Prunus avium); Oranges (Citrus × sinensis); Grapes (Vitis vinifera); Grapefruits (Citrus × paradisi); Apricots (Prunus armeniaca); Apples (Malus spp.); Tea (Camellia sinensis)	(82)
Kaempferol (21)	Aloe (Aloe vera); Ivy gourd (Coccinia grandis); Drumstick tree (Moringa oleifera); Broccoli (Brassica oleracea); French beans (Phaseolus vulgaris); Tea (Camellia sinensis); Strawberries (Fragaria × ananassa)	(83)

Figure 1. Chemical structures of the dietary polyphenols that modulate Keap1/Nrf2/ARE and interconnected signaling pathways. Here, (1) xanthohumol, (2) punicalagin, (3) resveratrol, (4) methyleugenol, (5) 6-shogaol, (6) chlorogenic acid, (7) ferulic acid, (8) carnosic acid, (9) carnosol, (10) ellagic acid, (11) apigenin, (12) catechin, (13) epicatechin, (14) EGCG, (15) fisetin, (16) genistein, (17) isoorientin, (18) quercetin, (19) luteolin, (20) rutin, and (21) kaempferol.

Figure 2. Cancer protective role of dietary polyphenols via modulating Keap1/Nrf2/ARE and interconnected signaling pathways.

Table 2. Cell signaling pathways and proteins targeted by the 21 selected dietary polyphenols with a cancer protective role.

Name	Signaling Pathways	Proteins	In-vitro activity on	In-vivo activity on	References
Xanthohumol (1)	p53, AMPK, STAT3, Akt, NF-κB	↑ HO-1, ↑ NQO1, ↑ GST, ↑ SOD, ↑ GSTP	Hepatocellular, pancreatic, chronic myeloid leukemia, colon, and prostate cancer	Pancreatic, leukemia	(84–90)
Punicalagin (2)	PI3/Akt, NF-κB, ERK	↑ HO-1	Cervical, osteosarcoma, and colon cancer	osteosarcoma	(91–94)
Resveratrol (3)	MAPK, PI3K/Akt, SIRT1, NF-κB, IKKβ, TGF-β1, Bax	↑ GST, ↑ HQO-1, ↑ HO-1, ↑ SOD-1, ↑ CAT, ↑ NQO1, ↑ OGG, ↑ GPx	Breast tumor, leukemia, renal, liver, and prostate cancer	Pancreatic, liver, colorectal, and breast cancer	(95–100)
Methyleugenol (4)	AMPK/GSK3b, ERK	↑ GCLC, ↑ GCLM, ↑ HO-1, ↑ NQO1	Cervical, retinoblastoma, leukemia, and colon cancer	N/A	(101–103)
6-Shogaol (5)	JNK, HO-1, COX2, iNOS, NF-κB, MAPK, PI3K/Akt	↑ AKR1B10, ↑ FTL, ↑ GGTLA4, ↑ HO-1, ↑ GCLC, ↑ GCLM, ↑ GCS, ↑ NQO1	Breast, lung, prostate, pancreatic, and endometrial cancer	Prostate, pancreatic, lung, and endometrial cancer	(104–110)
Chlorogenic acid (6)	NF-κB, IκBα, PI3K/Akt/mTOR, ERK1/2, p38 MAPK, JNK, HIF-1α/Akt, MMP-2 and -9, VEGF, EGF, IL-10, TGF-β, CD34	↑ GST, ↑ gGCL, ↑ NQO1, ↑ HO-1	Colon, breast, renal, lung, and hepatocellular carcinoma	Breast, lung, and hepatocellular carcinoma	(111–121)
Ferulic acid (7)	ERK1/2, NF-κB, IGF II, VEGF, PI3K-Akt	↑ HO-1, ↑ Bcl-2, ↑ NQO1, ↑ GSTA2, ↑ HO-1, ↑ PPARγ, ↓cyclin D1	Cervical, colorectal, prostate, melanoma, and breast cancer	Colorectal, melanoma, and breast cancer	(122–127)
Carnosic acid (8)	PI3K/Akt/mTOR, NF-κB, JNK, COX-2, JAK2-STAT3/Src-STAT3, TRAIL	↑ GSH, ↑ SOD, ↑ AKR1C2, ↑ HO-1, ↑ GDF15, ↑ PHLDA1, ↑ DDIT3, ↓Bcl-2, ↑ GCLC	Colorectal, breast, hepatocellular, gastric, and cervical cancer	Breast, hepatocellular, cervical, and liver cancer	(128–135)
Carnosol (9)	ERK, p38, JNK, PI3K, Sestrin2, MRP2, Akt, STAT3	↑ GSH, ↑ GCLC/GCLM, ↑ HO-1, ↑ NQO1	Colon, prostate, breast, and hepatocellular carcinoma	N/A	(136–139)
Ellagic acid (10)	ERK, JNK, PI3K/AKT/mTOR, STAT3, COX-2, NF-κB, AMPK, HIF-1α	↑ HO-1, ↑ SOD1, ↑ SOD2, ↑ GSH, ↑ γ-GCLC, ↑ NQO1	Endometrial, breast, prostate, pancreatic, bladder, and lung cancer	Endometrial, breast, pancreatic, bladder, and lung cancer	(140–145)
Apigenin (11)	MAPK, p38, ERK1/2 and JNK, PI3K/AKT/mTOR	↑ HO-1, ↑ SOD, ↑ CAT, ↑ GPx, ↑ NQO-1, ↓DNMT, ↓HDAC, ↑ GCLC, ↑ GCLM	Hepatocellular, skin, lung, prostate, colon, leukemia, and cervical cancer	Prostate, colon, leukemia, and cervical cancer	(70), (146–152)
Catechin (12)	ERK1/2, NF-κB, VEGF	↑ GCLC/GCLM, ↑ HO-1, ↑ NQO1, ↑ GPx, ↑ GR	Cervical, colon, and larynx carcinoma	N/A	(153–154)
Epicatechin (13)	PI3K/Akt, ERK, JNK1/2/3, p-38 MAPK, NF-κB, IL-10, IL-4	↑ SOD-1, ↑ GSH, ↑ HO-1, ↑ NQO1	Breast, colorectal, gastric, prostate, and leukemia	Leukemia	(155–159)
EGCG (14)	Akt, ERK1/2, p38, MAPK, Nrf2-UGT1A, VEGF, COX-2, IL-6, HIF-1α	↑ HO-1, ↑ GST, ↑ NQO1	Colorectal, lung, endometrial, and breast cancer	Colorectal, breast, esophageal, gastric, lung, neural, oral, and prostate cancer	(160–164)
Fisetin (15)	ERK, JNK, p38/MAPK, PI3K/Akt/mTOR, COX-2, Wnt/EGFR/NF-κB, eNOS, VEGF, iNOS	↑ HO-1, ↑ GCLC, ↑ GCLM, ↑ NQO1, ↑ GPx, ↓MDA, ↓cyclin D1, ↓survivin	Cholangiocarcinoma, oral, breast, bladder, colorectal, prostate, pancreatic, and cervical cancer	Breast, colorectal, pancreatic, and cervical cancer	(165–173)
Genistein (16)	ERK1/2, PKC, PI3K/Akt, SIRT1, NF-κB	↑ HO-1, ↑ NQO-1, ↑ SOD, ↑ CAT, ↑ GSH, ↑ GCLC, ↓Bcl-2	Prostate, pancreatic, breast, leukemia, bladder, and lung cancer	Pancreatic, leukemia, bladder, and lung cancer	(174–179)
Isoorientin (17)	SIRT1/SIRT6, AMPK/Akt/GSK3β, PI3K/Akt, JAK/STAT3, Wnt/β-catenin	↑ GCLC, ↑ GCLM, ↑ HO-1, ↑ NQO1, ↑ Trx-1	Liver, pancreatic, skin, lung, and oral cancer	Oral cancer	(180–184)
Quercetin (18)	p38-MAPK, PI3K/Akt/mTOR, STAT1, NF-κB, JNK/ERK MAPK	↑ GSH, ↑ GCS, ↑ GPx, ↑ GR, ↑ GCLC, ↓MDA, ↑ SOD, ↑ HO-1, ↑ CAT, ↑ GST, ↓Bcl-2	Liver, colon, breast, prostate, and mesothelioma	Prostate, and lung cancer	(80), (185–191)
Luteolin (19)	ERK1/2, NF-κB/p53, PI3K/Akt, mTOR, SIRT1, ROS/JNK, K-ras/GSK-3β/NF-κB	↑ HO-1, ↑ GCLC, ↑ GCLM, ↑ GSH, ↑ NQO1, ↑ SOD, ↑ GPx, ↑ CAT, ↓MDA, ↑ TRX1	Colorectal, lung, breast, bladder, and esophageal cancer	Breast, bladder, pancreatic, and esophageal cancer	(81), (192–200)
Rutin (20)	PI3K/Akt, SIRT1, STAT3/NF-κB, JNK, AP-1, and p38 MAPK, Wnt/β-catenin, COX-2, iNOS, TNF-α,	↑ HO-1, ↑ NQO-1, ↑ GST, ↑ Mn-SOD, ↓Bcl-2	Colon, lung, gastric, prostate, breast, brain, and leukemia	Cervical, breast, and colorectal cancer	(201–210)
Kaempferol (21)	p38, ERK1/2, JNK, SIRT1, PARP1, AMPK, PKCδ/MAPK/AP-1, IRS-1, Akt/ PI3K, MEK1/2, ERK-NFκB-cMyc-p21-VEGF, NF-κB	↓HO-1, ↑ SOD, ↑CAT, ↑ GSH, ↓NQO1, ↓AKR1C1, ↓GST	Pancreatic, hepatocellular, breast, cervical, colon, ovarian, and gastric cancer	Gastric, lung, and breast cancer	(211–220)

↑ indicates upregulation; ↓ indicates downregulation.

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