TABLE 1.
Current research status of therapeutic potentials targeting Nrf2-mediated oxidative stress response signaling pathways in different cancers.
| Cancer type | Experimental model | Chemical reagents or potential drugs | Possible mechanisms | References |
|---|---|---|---|---|
| Acute myeloid leukemia | Acute myeloid leukemia cells in a xenograft mouse model | Nrf2 activators: dimethyl fumarate (DMF), tert-butylhydroquinone, or carnosic acid | Cooperate with vitamin D derivatives to induce acute myeloid leukemia cell differentiation to inhibit leukemia progression in a xenograft mouse model via activating the Nrf2/ARE signaling pathway | Nachliely et al. (2019) |
| Human acute myeloid leukemia cells | Novel pyrazolyl hydroxamic acid derivative (4f) | Inhibit Nrf2 activity to induce apoptosis of human acute myeloid leukemia cells | Zhang et al. (2019) | |
| Gallbladder cancer | Gallbladder cancer cells | The aPKCι inhitors, Nrf2 activators, or gemcitabine | Atypical protein kinase Cι (aPKCι) can promote gallbladder tumorigenesis and chemoresistance of anticancer agent gemcitabine by competing with Nrf2 for binding to Keap1, implying that inhibiting the aPKCι-Keap1-Nrf2 axis might overcome drug resistance for the gallbladder cancer treatment | Tian et al. (2019) |
| Renal carcinoma | Human renal carcinoma cells | Chitosan oligosaccharide (COS) | Inhibit human renal carcinoma cell proliferation in vitro and in vivo by promoting the expressions of Nrf2 and Nrf2 target genes such as HO-1, the modifier subunit of glutamate cysteine ligase, solute carrier family 7 member 11, glucose-regulated protein 78, protein RNA-like endoplasmic reticulum kinase, and cytochrome C,etc. | Zhai et al. (2019) |
| Pancreatic cancer | Pancreatic cancer cells | Resveratrol | Enhance the sensitivity of pancreatic cancer cells to gemcitabine via suppressing NAF-1 expression, inducing ROS accumulation, and activating Nrf2 signaling pathways | Cheng et al. (2018) |
| Melanoma | Melanoma cells | Nrf2 inhibitor: Brusatol (BR) | The co-treatment of brusatol and UVA irradiation can effectively inhibit melanoma growth by regulating the AKT-Nrf2 pathway | Wang et al. (2018) |
| Hepatocellular carcinoma | Hepatocellular carcinoma (HCC) cells | Vitamin C (VC), all-trans retinoic acid (ATRA), ochratoxin A (OTA), bexarotene, flavonoids (including brusatol, luteolin, apigenin and chrysin), ruthenium (Ru) metal complexes, ursolic acid (UA), halofuginone, trigonelline, quercetin, and isoniazid | Sensitize chemotherapy drugs in hepatocellular carcinoma | Tian et al. (2018) |
| Mouse hepatocellular carcinoma model | Cordycepin (CA) | Activate the Nrf2/HO-1/NF-κB pathway for its anti-hepatocarcinoma effect in N-nitrosodiethylamine (NDEA)-induced mouse hepatocellular carcinomas | Zeng et al. (2017) | |
| Hep3B (human hepatoma cell) and HL-7702 (normal human liver cell) cell lines | Novel indazolo[3,2-b] quinazolinone (IQ) derivatives: IQ-7 and IQ-12 | Induce apoptosis and inhibit the Nrf2/ARE signaling pathway in Hep3B cells, and IQ-7 was suggested a degree of specificity against cancer cells. | Zhang et al. (2016) | |
| Liver injury mouse model | Dibenzoylmethane (DBM) | Protect against carbon tetrachloride (CCl4)-induced liver injury by activating Nrf2 signaling via JNK, AMPK, and calcium signaling | Cao et al. (2017) | |
| Lung cancer | Lung cancer cells | The potent anticancer agent: Isodeoxyelephantopin | Induce protective autophagy in lung cancer cells via the Nrf2-p62-keap1 pathway | Wang et al. (2017) |
| RAW 264.7 mouse macrophage-like cells, in VC1 lung cancer cells, and in the A/J model of lung cancer | Two clinically relevant classes of Nrf2 activators: DMF, and the synthetic oleanane triterpenoids –C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO)-Imidazolide (CDDO-Im) and CDDO-Methyl ester (CDDO-Me) | Activate the Nrf2 pathway as well as regulate different subsets of Nrf2 target genes and Nrf2-independent genes | Chian et al. (2014) and To et al. (2015) | |
| Colon cancer | SFN-treated human colon cancer cells and non-transformed colonic epithelial cells | Anticancer agent: Sulforaphane (SFN) | Regulate the activity of antioxidant and the detoxification of carcinogens via Nrf2 signaling to suppress human colon cancer | Johnson et al. (2017) |
| 1, 2-dimethyl hydrazine (DMH)-induced mouse colon model | Taxifolin (TAX) | Induce antioxidant response pathway, enhance level of Nrf2 proteins, and act as effective chemopreventive agent capable of modulating inflammatory | Manigandan et al. (2015) | |
| Ovarian cancer | Human ovarian cancer cell lines: PEO4, OVCAR4, and SKOV3 | Anti-HER2 drugs: Trastuzumab and Pertuzumab | HER2 targeting by antibodies inhibited growth in association with persistent ROS generation, glutathione (GSH) depletion, reduction in NRF2 levels, and inhibition of NRF2 function in ovarian cancer cell lines | Khalil et al. (2016) |
| Human epithelial ovarian cancer (EOC) cell lines | Keap1 mutation reagent | Activation of Nrf2 pathway in EOC seems to be related to Keap1 mutations within highly conserved domains of the Keap1 gene; and Nrf2 may serve as an important therapeutic target for novel drugs capable of preventing or reversing resistance to chemotherapy in EOC | Konstantinopoulos et al. (2011) | |
| Breast cancer | Breast cancer cells, and mouse model | Target antioxidant enzymes: GCLC and GCLM | Nrf2 serves as a key regulator in chemotherapeutic resistance under hypoxia through ROS-Nrf2-GCLC-GSH pathway, and can be a potential treatment for hypoxia-induced drug resistance in breast cancer cells. | Syu et al. (2016) and Song et al. (2011) |
| Esophageal cancer | Esophageal squamous cancer cells (ESCC): Ec109 and KYSE70 cells | CDDO-Me | Protects the cells against oxidative stress via inhibition of ROS generation, while CDDO-Me at low micromolar concentrations induces apoptosis by increasing ROS and decreasing intracellular glutathione levels | Wang X. et al. (2015) |
| Glioblastoma | Glioblastoma cells | Potential anti-cancer agents | Targeting Nrf2 signaling for chemotherapy and chemoresistance | Zhu et al. (2014) |
| Osteosarcoma | Human osteosarcoma 143B and MG63 cells | The bioengineered Nrf2-siRNA | Interfere with the Nrf2 signaling pathway to reduce the expression of NRF2-regulated oxidative enzymes and lead to higher intracellular ROS levels; knocking down NRF2 with bioengineered siRNA agent improves chemosensitivity of cancer cells, which is related to the suppression of NRF2-regulated efflux ABC transporters. | Li et al. (2018) |
| Other cancers | prostate cancer cell PC4-LN4; colon cancer cell HCT-116; breast cancer cells MB-MDA-231 and MB-MDA-231-ARE-Luc | PIM kinases inhibitors | Inhibit Nrf2 signaling and increase ROS to kill hypoxic tumor cells in a HIF-1-independent manner by controlling its cellular localization | Warfel et al. (2016) |
| Mammalian cancer cells | Proteasome inhibitors | In response to proteasome inhibition, several responses are activated, such as the ALP, proteaphagy, the transcriptional upregulation of the autophagy Ubreceptor p62/SQSTM1, and proteasome genes, by Nrf1 and Nrf1/Nrf2 transcription factors, respectively. | Albornoz et al. (2019) | |
| Mouse epidermal cells (JB6 P+), | Gallic acid (GA), Z-ligustilide (LIG), and senkyunolide A (SA) | GA, LIG, and SA in Si-Wu-Tang (SWT) can individually or cooperatively target the Nrf2/ARE pathway to prevent cancer. | Liu et al. (2018) |
ALP, Autophagic-Lysosomal Pathway; ATRA, All-trans retinoic acid; BR, Brusatol; CA, Cordycepin; CDDO, C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; COS, Chitosan oligosaccharide; DBM, Dibenzoylmethane; DMF, dimethyl fumarate; GA, Gallic acid; IQ, Indazolo[3,2-b] quinazolinone; LIG, Z-ligustilide; OTA, Ochratoxin A; PIM, The Proviral Integration site for Moloney murine leukemia virus; Ru, Ruthenium; SA, Senkyunolide A; SFN, Sulforaphane; TAX, Taxifolin; UA, Ursolic acid; VC, vitamin C.