Source: TCGA |
Type: Antiapoptotic |
Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response. -One way to estimate Nrf2 induction is through the expression of NQO1. NQO1, the most potent inducer: SFN 0.2 μM, quercetin (2.5 μM), curcumin (2.7 μM), Silymarin (3.6 μM), tamoxifen (5.9 μM), genistein (6.2 μM ), beta-carotene (7.2μM), lutein (17 μM), resveratrol (21 μM), indol-3-carbinol (50 μM), chlorophyll (250 μM), alpha-cryptoxanthin (1.8 mM), and zeaxanthin (2.2 mM) 1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects. 2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death. 3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress -In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies. -Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate. Decreased Nrf2 expression: Skine, Liver, Pancreatic. -Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer - "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1. Nrf2 Inhibitors and Activators Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api - potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue. – In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis. – In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity. – This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming. – Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies. – High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types. – While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression. NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS). -Brusatol: most cited natural inhibitors of Nrf2. -Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent. -Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent . -Oridonin: -Wogonin: although its effects might be cell‑ and dose‑specific. - Withaferin A |
256- | AL, | doxoR, | Allicin Overcomes Doxorubicin Resistance of Breast Cancer Cells by Targeting the Nrf2 Pathway |
- | in-vitro, | BC, | MCF-7 | - | in-vitro, | BC, | MDA-MB-231 |
267- | ALA, | α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells |
- | vitro+vivo, | Lung, | A549 | - | vitro+vivo, | Lung, | PC9 |
265- | ALA, | Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies |
- | in-vitro, | Pca, | LNCaP | - | in-vitro, | Pca, | DU145 |
2586- | Api, | doxoR, | Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway |
- | in-vitro, | HCC, | Bel-7402 |
2593- | Api, | Apigenin promotes apoptosis of 4T1 cells through PI3K/AKT/Nrf2 pathway and improves tumor immune microenvironment in vivo |
- | in-vivo, | BC, | 4T1 |
2594- | Api, | docx, | Targeted hyaluronic acid-based lipid nanoparticle for apigenin delivery to induce Nrf2-dependent apoptosis in lung cancer cells |
- | in-vitro, | Lung, | A549 |
2596- | Api, | LT, | Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment |
- | Review, | Var, | NA |
2639- | Api, | Plant flavone apigenin: An emerging anticancer agent |
- | Review, | Var, | NA |
1547- | Api, | Apigenin: Molecular Mechanisms and Therapeutic Potential against Cancer Spreading |
- | Review, | NA, | NA |
1358- | Ash, | Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms |
- | Review, | Var, | NA |
3172- | Ash, | Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis |
- | in-vitro, | HCC, | HepG2 | - | in-vitro, | Nor, | HL7702 |
2627- | Ba, | Cisplatin, | Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways |
2617- | Ba, | Potential of baicalein in the prevention and treatment of cancer: A scientometric analyses based review |
- | Review, | Var, | NA |
2296- | Ba, | The most recent progress of baicalein in its anti-neoplastic effects and mechanisms |
- | Review, | Var, | NA |
2021- | BBR, | Berberine: An Important Emphasis on Its Anticancer Effects through Modulation of Various Cell Signaling Pathways |
- | Review, | NA, | NA |
1392- | BBR, | Based on network pharmacology and experimental validation, berberine can inhibit the progression of gastric cancer by modulating oxidative stress |
- | in-vitro, | GC, | AGS | - | in-vitro, | GC, | MKN45 |
1389- | BBR, | Lap, | Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS |
- | in-vitro, | BC, | BT474 | - | in-vitro, | BC, | AU-565 |
2756- | BetA, | Betulinic acid inhibits growth of hepatoma cells through activating the NCOA4-mediated ferritinophagy pathway |
- | in-vitro, | HCC, | HUH7 | - | in-vitro, | HCC, | H1299 |
738- | Bor, | Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways |
- | in-vitro, | GBM, | U251 | - | in-vitro, | GBM, | A172 | - | in-vitro, | Nor, | SVGp12 |
2591- | CHr, | doxoR, | Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway |
- | in-vitro, | HCC, | Bel-7402 |
2590- | CHr, | Chrysin suppresses proliferation, migration, and invasion in glioblastoma cell lines via mediating the ERK/Nrf2 signaling pathway |
- | in-vitro, | GBM, | T98G | - | in-vitro, | GBM, | U251 | - | in-vitro, | GBM, | U87MG |
2781- | CHr, | PBG, | Chrysin a promising anticancer agent: recent perspectives |
- | Review, | Var, | NA |
2782- | CHr, | Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives |
- | Review, | Var, | NA | - | Review, | Stroke, | NA | - | Review, | Park, | NA |
2785- | CHr, | Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin |
- | Review, | Var, | NA |
2786- | CHr, | Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives |
- | Review, | Var, | NA |
1410- | CUR, | Curcumin induces ferroptosis and apoptosis in osteosarcoma cells by regulating Nrf2/GPX4 signaling pathway |
- | vitro+vivo, | OS, | MG63 |
1844- | dietFMD, | Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment |
- | Review, | NA, | NA |
3214- | EGCG, | EGCG-induced selective death of cancer cells through autophagy-dependent regulation of the p62-mediated antioxidant survival pathway |
- | in-vitro, | Nor, | MRC-5 | - | in-vitro, | Cerv, | HeLa | - | in-vitro, | Nor, | HEK293 | - | in-vitro, | BC, | MDA-MB-231 | - | in-vitro, | CRC, | HCT116 |
2845- | FIS, | Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy |
- | Review, | Var, | NA |
2852- | FIS, | A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms |
- | Review, | CRC, | NA |
2838- | FIS, | Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2) |
2916- | LT, | Antioxidative and Anticancer Potential of Luteolin: A Comprehensive Approach Against Wide Range of Human Malignancies |
- | Review, | Var, | NA | - | Review, | AD, | NA | - | Review, | Park, | NA |
2919- | LT, | Luteolin as a potential therapeutic candidate for lung cancer: Emerging preclinical evidence |
- | Review, | Var, | NA |
2930- | LT, | Luteolin confers renoprotection against ischemia–reperfusion injury via involving Nrf2 pathway and regulating miR320 |
- | in-vitro, | Nor, | NA |
2914- | LT, | Therapeutic Potential of Luteolin on Cancer |
- | Review, | Var, | NA |
2595- | LT, | Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management? |
- | Review, | Var, | NA |
2589- | LT, | Chemo, | Luteolin Inhibits Breast Cancer Stemness and Enhances Chemosensitivity through the Nrf2-Mediated Pathway |
- | in-vitro, | BC, | MDA-MB-231 |
2588- | LT, | Chemo, | Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway |
- | in-vitro, | CRC, | HCT116 |
2587- | LT, | Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs |
- | in-vitro, | Lung, | A549 |
3828- | Lyco, | Lycopene alleviates oxidative stress via the PI3K/Akt/Nrf2pathway in a cell model of Alzheimer's disease |
- | in-vitro, | AD, | M146L |
1204- | MET, | Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer |
- | in-vitro, | Lung, | A549 | - | in-vitro, | Lung, | H1299 |
- | in-vitro, | AD, | NA |
1273- | Myr, | Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4 |
- | vitro+vivo, | GC, | NA |
3251- | PBG, | The Antioxidant and Anti-Inflammatory Effects of Flavonoids from Propolis via Nrf2 and NF-κB Pathways |
- | Review, | AD, | NA | - | Review, | Diabetic, | NA | - | Review, | Var, | NA | - | in-vitro, | Nor, | H9c2 |
2961- | PL, | Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis |
- | in-vitro, | ESCC, | KYSE-30 |
3054- | RES, | Resveratrol induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line |
- | in-vitro, | Melanoma, | A375 |
1688- | Se, | Potential Role of Selenium in the Treatment of Cancer and Viral Infections |
- | Review, | Var, | NA |
1280- | SK, | Shikonin Induces Apoptotic Cell Death via Regulation of p53 and Nrf2 in AGS Human Stomach Carcinoma Cells |
- | in-vitro, | GC, | AGS |
1346- | SK, | An Oxidative Stress Mechanism of Shikonin in Human Glioma Cells |
- | in-vitro, | GBM, | U87MG | - | in-vitro, | GBM, | Hs683 |
2201- | SK, | Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice |
- | in-vitro, | PSA, | HaCaT | - | in-vivo, | NA, | NA |
2198- | SK, | Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis |
- | in-vitro, | OS, | MG63 | - | in-vitro, | OS, | 143B |
2197- | SK, | Shikonin derivatives for cancer prevention and therapy |
- | Review, | Var, | NA |
365- | SNP, | Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species |
- | in-vitro, | Hepat, | HepG2 |
3415- | TQ, | The anti-neoplastic impact of thymoquinone from Nigella sativa on small cell lung cancer: In vitro and in vivo investigations |
- | in-vitro, | Lung, | H446 |
2132- | TQ, | Thymoquinone treatment modulates the Nrf2/HO-1 signaling pathway and abrogates the inflammatory response in an animal model of lung fibrosis |
- | in-vivo, | Nor, | NA |
2454- | Trip, | Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ |
- | in-vitro, | HNSCC, | HaCaT | - | in-vivo, | NA, | NA |
3108- | VitC, | QC, | The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells |
- | in-vitro, | BC, | MDA-MB-231 | - | in-vitro, | Lung, | A549 |
2592- | VitC, | Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line |
- | in-vitro, | CLL, | NA |
114- | VitC, | QC, | Chemoprevention of prostate cancer cells by vitamin C plus quercetin: role of Nrf2 in inducing oxidative stress |
- | in-vitro, | Pca, | PC3 | - | in-vitro, | NA, | DU145 |
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