Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals
Abstract
:1. Introduction
2. Oxidative Stress and Lipid Peroxidation in Colon Carcinogenesis
2.1. 4-Hydroxynonenal
2.2. Acrolein
Lipid Peroxidation Products | Model | Mode of Action | Reference |
---|---|---|---|
4-hydroxynonenal | CaCO-2 | 4-hydroxynonenal ↓ TGF-βI ↓ Apoptosis ↓ | [27] |
APC+/+ APCMin/+ (colon epithelial cell) | 4-hydroxynonenal metabolism ↑ (APCMin/+) Aldehyde dehydrogenase 1A1, 2, 3A1 ↑ (APCMin/+) Glutathione transferase A4-4 ↑ (APCMin/+) Cystine transporter XCT ↑ (APCMin/+) | [25] | |
Acrolein | HT29 | Apoptosis ↑ (acrolein 150, 200 μM) DNA adduct ↑ | [36] |
CCD-841CoN | p-EGFP ↑ (acrolein 5 μM, 8 h) RAS ↑ (acrolein 5 μM, 8 h) p-AKT ↑ (acrolein 5 μM, 8 h) p-ERK ↑ (acrolein 5 μM, 8 h) Cyclin D1 ↑ (acrolein 5 μM, 8 h) | [37] | |
CRC patients | Acr-dG ↑ (in tumor) Over survival (high Acr-dG > low Acr-dG) | [37] | |
APCMin/+ | Cocalent adduct with PTEN ↑ pser473Akt ↑ | [38] |
3. Antioxidative Nrf2/KEAP1 Signaling Pathway
3.1. Nrf2
3.2. KEAP1
3.3. Antioxidative Effect by Nrf2/KEAP1 Signal
3.4. Nrf2/KEAP1-Dependent Regulation of Antioxidative Enzymes
3.4.1. Superoxide Dismutase
3.4.2. Catalase
3.4.3. Glutathione Peroxidase
3.4.4. Glutathione
3.4.5. Heme Oxygenase-1
3.4.6. NAD(P)H Quinone Oxidoreductase 1
4. Regulation of Nrf2/KEAP1 by Phytochemicals in Colorectal Cancer
4.1. Epigallocatechin-3-Gallate
4.2. Sulforaphane
4.3. Curcumin
4.4. Luteolin
4.5. Allicin
4.6. Resveratrol
4.7. Nobiletin
4.8. Genistein
4.9. Miscellaneous
Phytochemicals | Effective Dose (Periods) | Experimental Model | Mode of Action | Reference |
---|---|---|---|---|
EGCG | 20 mg/kg (6 weeks) | BalB/cA nude mouse | Nrf2 mRNA levels ↑ UGT mRNA levels ↑ Phase II drug metabolizing enzymes ↑ | [128] |
5, 10, 20 mg/kg (4 weeks) | BalB/cA nude mouse | Nrf2 protein levels ↑ Nrf2 mRNA levels ↑ UGT1A, UGT1A8 and UGT1A10 mRNA levels ↑ Liver and lung metastasis (20 mg/kg) ↓ | [129] | |
12.5 μM | HCT-116 cell | Cell growth ↓ Colony formation ↓ Nrf2 nuclear translocation ↑ LC3B protein levels ↑ Caspase-9 protein levels ↑ | [130] | |
SFN | 0, 1, 10 μM | HCT-116 | Nrf2 protein levels ↑ HO-1 protein levels ↑ mtDNA/nDNA ratio (p53 KO) ↓ PGC-1α (p53 KO) ↓ | [134] |
2.5, 10, 25 mg/kg | p53 wildtype (WT) and p53 knockout (KO) BalB/c nude mouse | Nrf2 protein levels (p53 KO) ↑ Bcl-2 protein levels (p53 KO) ↓ Cytochrome C (p53 KO) ↑ | [134] | |
5, 10, 15, 20 μM | HT29 and SW480 cell | Nrf2 protein levels ↑ UGT1A protein levels ↑ Cell proliferation ↓ Cell migration ↓ Colony formation ↓ Apoptosis ↑ | [136] | |
Curcumin | 1000 mg/kg (single oral dose) | Nrf2 WT and Nrf2 KO C57BL/6J mouse | HO-1 mRNA levels ↑ UGT2B5 mRNA levels ↑ Carbonyl reductase 3 ↑ | [139] |
Luteolin | 20, 40 μM | HT29 cell | ROS ↑ Cytochrome C protein levels ↑ Bax protein levels ↑ Bcl-2 protein levels ↓ Caspase-3 protein levels ↑ Nrf2 nuclear translocation ↑ Cell proliferation ↓ | [142] |
10, 30, 60 μM | HT29 and SNU-407 cell | Methylation of Nrf2 promoter ↓ GCLC protein levels ↑ GSS protein levels ↑ Catalase protein levels ↑ HO-1 protein levels ↑ Bax protein levels ↑ Bcl-2 protein levels ↓ Cleaved caspase-3 protein levels ↑ Cleaved caspase-9 protein levels ↑ Cell viability ↓ | [143] | |
Allicin | 10 μg/ml | HCT-116 cell | Nrf2 protein levels ↑ Nrf2 promoter activity ↑ Cytochrome C ↑ Bax protein levels ↑ Bcl-2 protein levels ↓ | [146] |
Resveratrol | 250 ppm | BalB/c mouse (AOM model) | Nrf2 protein levels ↑ HO-1 protein levels ↑ Glutathione reductase mRNA levels ↑ | [151] |
20, 50 μM | IPEC-J2 cell (H2O2-induced intestinal barrier injury) | Cell viability ↑ SOD activity ↑ CAT activity ↑ GSH activity ↑ SOD mRNA levels ↑ CAT mRNA levels ↑ HO-1 mRNA levels ↑ Nrf2 mRNA levels ↑ | [152] | |
Nobiletin | AIN93G diet containing 0.05% nobiletin | CD-1 mouse (AOM/DSS model) | Nrf2 nuclear translocation ↑ Nrf2 protein levels ↑ HO-1 protein levels ↑ NQO-1 protein levels ↑ Cell cycle arrest | [155] |
Genistein | 2.5 mg/kg body weight (6 weeks) | Wistar rat (dimethylhydrazine-induced colon carcinogenesis) | Nrf2 expression ↑ HO-1 expression ↑ Glutathione levels ↑ NADPH levels ↑ | [156] |
Baicalein | 40 μM | HCT-116 cell | Nrf2 phosphorylation ↓ | [157] |
50, 100, 150, 200 μM | HT29, SW480, HCT-116, and SW620 cell | Cell viability ↓ LC3-II protein levels ↑ (HCT-116) Caspase-3/7 activity ↑ (HCT-116) | [158] | |
Wogonin | 60 mg/kg (29, 48, 68, 105 days) | C57BL/6 mouse (AOM/DSS model) | Nrf2 nuclear translocation ↑ Nrf2 positive cells ↑ | [160] |
25, 50, 100 μM | HCT-116 cell | IL-6, IL-6, IL-1β levels ↓ HO-1 protein levels ↑ NQO1 protein levels ↑ KEAP1 protein levels ↑ Nrf2 promoter activity ↑ | ||
Oroxylin A | 50, 100, 150 μM | HCT-116 cell | Cell proliferation ↓ Bax protein levels ↑ Bcl-2 protein levels ↓ Nrf2 nuclear translocation ↑ HO-1 protein levels ↑ NQO1 protein levels ↑ | [161] |
50, 100, 200 mg/kg | Balb/c mouse | Nrf2 nuclear translocation ↑ | ||
Ginnalin A | 20, 40, 80 μM | HCT-116, SW480, and SW620 cell | Cell proliferation ↓ S-phase cell cycle arrest Nrf2 mRNA and protein levels ↑ HO-1 mRNA and protein levels ↑ NQO1 mRNA and protein levels ↑ KEAP1 protein levels ↓ | [162] |
5. Clinical Trials of Phytochemicals in Patients with Colorectal Cancer
Phytochemicals | Dosage (Periods) | Phase | Results | NCT Number | Reference |
---|---|---|---|---|---|
EGCG | 900 mg (1 year) | I, II | Chemoprevention | NCT02891538 | - |
Curcumin | 4 g | I | Chemoprevention | NCT01490996 | - |
2, 4 g (30 days) | II | Aberrant crypt foci ↓ | - | [165] | |
Resveratrol | 20, 80 g | I | Wnt signaling pathway regulation | NCT00256334 | [166] |
Genistein | 60 mg (2 weeks) | No observation of side effects with/without FOLFOX or FOLFOX-Bevacizumab | NCT01985763 | [167] |
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Acr-dG | Acrolein-induced DNA damages |
APC | Adenomatous polyposis coli |
ARE/EpRE | Antioxidant/electrophile responsive element |
BTB | Broad complex/Tramtrack/Bric-a-brac |
bZIP | Basic leucine zipper |
CAC | Colitis-associated colorectal cancer |
CBP | CREB-binding protein |
CD | Crohn’s disease |
CHD6 | Chromo-ATPase/helicase DNA-binding protein 6 |
CNC | Cap ’N’ Collar |
CRC | Colorectal cancer |
CREB | cAMP response element binding protein |
Cul3 | Cullin 3 |
DGR | Double glycine-repeat |
EGCG | Epigallocatechin-3-Gallate |
EGFR | Epithelial growth factor receptor |
ERK | Extracellular-signal-regulated kinase |
GCLC | Glutamate-cysteine ligase catalytic subunit |
GCLM | Glutamate-cysteine ligase modifier subunit |
GPx | Glutathione peroxidase |
GSH | Glutathione |
GSK | Glycogen synthase kinase |
GST | Glutathione-S-transferase |
HO | Heme oxygenase |
IBD | Inflammatory bowel disease |
IVR | Intervening region |
KEAP1 | Kelch-like-ECH-associated protein 1 |
NADPH | Nicotinamide adenine dinucleotide phosphate |
Neh | Nrf2-ECH homology |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
NQO1 | NAD(P)H quinone oxidoreductase 1 |
PTEN | Phosphatase and tensin homolog |
PUFA | Polyunsaturated fatty acids |
ROS | Reactive oxygen species |
SFN | Sulforaphane |
sMAF | Small musculoaponeurotic fibrosarcoma protein |
SOD | Superoxide dismutase |
TGF-βRI | Transforming growth factor-beta receptor I |
β-TrCP | β-transducin repeat-containing protein |
UbcM2 | Ubiquitin-conjugating enzyme |
UC | Ulcerative colitis |
UGT | UDP-glucuronosyltransferases |
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Lee, D.-Y.; Song, M.-Y.; Kim, E.-H. Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals. Antioxidants 2021, 10, 743. https://doi.org/10.3390/antiox10050743
Lee D-Y, Song M-Y, Kim E-H. Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals. Antioxidants. 2021; 10(5):743. https://doi.org/10.3390/antiox10050743
Chicago/Turabian StyleLee, Da-Young, Moon-Young Song, and Eun-Hee Kim. 2021. "Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals" Antioxidants 10, no. 5: 743. https://doi.org/10.3390/antiox10050743
APA StyleLee, D.-Y., Song, M.-Y., & Kim, E.-H. (2021). Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals. Antioxidants, 10(5), 743. https://doi.org/10.3390/antiox10050743