Table 2.

Flavonoids: Nrf2/ARE regulation in cancer cells.

Sub-Group	Compound	Effective Concentration/Concentration Range	Model	Mode of Action	Reference
Flavone	Luteolin	30 µM	Human colorectal carcinoma HCT116 cells	↑ mRNA expression of Nrf2. ↑ Nrf2 protein.	[211]
		10–15 µM	Human epithelial colorectal adenocarcinoma Caco-2 cells	↑ Nrf2 nuclear translocation. ↑ GSH levels.	[72]
		1.2 mg/kg body weight/day intraperitoneal injection once a week for 3 weeks	Colorectal cancer in Balb/C mice	↑ Nrf2 and GST proteins.	[200]
		1.5–6.25 µM	Human hepatocellular carcinoma HepG2 cells	↑ mRNA and protein expression of Nrf2 and HO-1 via PI3K/Akt.	[65]
		1–10 µM	Human epithelial colorectal adenocarcinoma Caco-2 cells	↓ mRNA expression of Nrf2, HO-1, NQO-1, aldo-keto reductases1C1 and C2 (AKR1C), glutamate-cysteine ligase catalytic subunit (GCLC), and multidrug resistance-associated protein (MRP) 2.	[61]
		5–10 µM	Human alveolar basal epithelial adenocarcinoma A549 cells	↓ mRNA expression of HO-1, NQO-1, AKR1C, GCLC, and MRP2. ↓ Nrf2 protein.	[61]
		1–10 µM	Human breast cancer MCF7 cells	↓ mRNA expression of Nrf2, HO-1, NQO-1, AKR1C, GCLC, and MRP2.	[61]
		25 µM	Opisthorchiasis-associated cholangiocarcinoma KKU-100 cells	↓ Nrf2, gamma-glutamylcysteine ligase and HO-1 proteins	[60]
	Chrysin	10–20 µM	Hepatocellular carcinoma BEL-7402/ADM cells	↓ mRNA and protein expression of Nrf2, HO-1, MRP5, and aldo-keto reductase family 1 member B10 (AKR1B10)	[63]
		20 µM	Human breast cancer MCF7 cells	↓ mRNA expression of Nrf2, MRP1, NQO-1, and HO-1.	[209]
	Apigenin	1.56–6.25 µM	Human hepatocellular carcinoma HepG2 cells	↑ mRNA expression of Nrf2. ↑ Nrf2 and HO-1 proteins. ↑ mRNA expression of Nrf2 and HO-1. Activates PI3K/Akt and ERK1/2 signaling.	[65]
		10–20 µM	Hepatocellular carcinoma BEL-7402/ADM cells	↓ mRNA expression of Nrf2. ↓ mRNA and protein expression of HO-1, MRP5, and AKR1B10.	[62]
		100 µM	Human hepatocellular carcinoma HepG2 cells	↓ mRNA expression of GSH and GPx. ↓ GSH and GPx activity.	[68]
	Tangeretin	20 µM	Human hepatocellular carcinoma HepG2 cells	↑ Nrf2 nuclear translocation ↑mRNA and protein expression of HO-1 and NQO-1.	[212]
Flavonol	Myricetin	10–40 µM	Human hepatocellular carcinoma HepG2 cells	Activates Nrf2 by modifying Keap1 protein. ↓ Nrf2 ubiquitination. ↑ Nrf2 nuclear translocation. ↑ ARE binding ability. ↑ Nrf2 protein levels but not Keap1. ↑ protein expression of HO-1.	[203]
	Quercetin	10 µM	Human hepatocellular carcinoma HepG2 cells	↑ Nrf2 nuclear translocation. ↑ARE binding activity of Nrf2.	[204]
		10 µM	Human neuroblastoma SH-SY5Y cells	↑ Nrf2 nuclear translocation. ↑ Nrf2 phosphorylation via PKC activation. ↑ protein and mRNA expression of glyoxalase-1. ↑ glyoxalase-1 activity	[123]
	Rutin	44 µM	Human epithelial colorectal adenocarcinoma Caco-2 cells	↑ mRNA expression of Nrf2, HO-1 and NQO-1 without changing Keap1 mRNA levels.	[140]
Flavanone	Hesperetin	40 µM	Murine macrophage Raw 264.7 cells	↑ Nrf2 nuclear translocation. ↑ degradation of Keap1. ↑ protein expression of HO-1	[205]
	Neohesperidin dihydrochalcone	30 µM	Human hepatocellular carcinoma HepG2 cells	↑ Keap1 modifications ↑ Nrf2 nuclear translocation. ↑ Nrf2 ARE binding ability. ↓ Nrf2 ubiquitination. ↑ phosphorylated JNK and p38 dependent protein expression of HO-1 and NQO-1.	[207]
	Naringenin	20–80 µM	Human neuroblastoma SH-SY5Y cells	↑ Nrf2 nuclear translocation. ↑ GSH protein ↑ protein expression of HO-1	[112]
Flavan-3-ol	Epicatechin	10 µM	Human hepatocellular carcinoma HepG2 cells	↑ Nrf2 phosphorylation. ↑ Nrf2 nuclear translocation.	[213]
	Morin	5–10 µM	Rat insulinoma INS-1E cells	↑ Nrf2 phosphorylation. ↑ Nrf2 nuclear translocation.	[214]
Isoflavones	Daidzein	5 µM	Murine hepatoma Hepa-1c1c7 cells	↑ mRNA expression of quinone reductase. ↑ quinone reductase activity. ↑ ARE binding ability	[208]
	Genistein	5 µM	Murine hepatoma Hepa-1c1c7 cells	↑ mRNA expression of quinone reductase. ↑ quinone reductase activity. ↑ ARE binding ability.	[208]
Chalcone	Phloretamide	20 µM	Human hepatocellular carcinoma HepG2 cells	↑ Nrf2 nuclear translocation. ↑mRNA expression of GST and NQO-1.	[215]

Abbreviations—HCT116: human colorectal carcinoma cell line; Caco-2: human epithelial colorectal adenocarcinoma cell line; KKU-100: opisthorchiasis-associated cholangiocarcinoma cell line; A549: human alveolar basal epithelial adenocarcinoma cell line; MCF7: human breast cancer cell line; BEL-7402/ADM: hepatocellular carcinoma cell line; HepG2: human hepatocellular carcinoma cell line; SH-SY5Y: human neuroblastoma cells; Raw 264.7: murine macrophage cell line; INS-1E: rat insulinoma cell line; Hepa-1c1c7: murine hepatoma cell line; GST: glutathione S-transferase; NQO-1: NAD(P)H quinone dehydrogenase 1; HO-1: heme oxygenase 1; AKR1C: aldo-keto reductases1 C1 and C2; GCLC: glutamate-cysteine ligase catalytic subunit; MRP: multidrug resistance-associated protein; AKR1B10: aldo-keto reductase family 1 member B10; PKC: protein kinase C; ERK: extracellular signal-regulated protein kinase; PI3K/Akt: phosphorylation of phosphatidylinositol 3-kinase/protein kinase B; JNK: N terminal kinase; Keap1: Kelch-like ECH-associated protein 1; Nrf2: Nuclear factor erythroid 2 p45 (NF-E2)-related factor; ↑ increase; ↓ decrease.