An Update of Nrf2 Activators and Inhibitors in Cancer Prevention/promotion

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2022 Jun 30

PMID 35773670

Authors

Farhad Pouremamali

Amir Pouremamali

Mehdi Dadashpour

Narges Soozangar

Farhad Jeddi

Affiliations

Soon will be listed here.

Abstract

NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can increase the sensitivity of the cells to oxidants and electrophiles. Transient Nrf2 activation, by its specific activators, has protective roles against carcinogenesis and cancer development. However, permanent activation of Nrf2 promotes various cancer properties, comprising malignant progression, chemo/radio resistance, and poor patient prognosis. Taken together, these findings suggest that reaching an optimal balance between paradoxical functions of Nrf2 in malignancy may render a selective improvement to identify therapeutic strategies in cancer treatment. In this review, we describe lately discovered Nrf2 inducers and inhibitors, and their chemopreventive and/or anticancer activities.

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References

Zhang D, Hannink M . Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol. 2003; 23(22):8137-51. PMC: 262403. DOI: 10.1128/MCB.23.22.8137-8151.2003. View

Nioi P, Nguyen T . A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun. 2007; 362(4):816-21. DOI: 10.1016/j.bbrc.2007.08.051. View

Patel D, Shukla S, Gupta S . Apigenin and cancer chemoprevention: progress, potential and promise (review). Int J Oncol. 2006; 30(1):233-45. View

Javan Maasomi Z, Pilehvar Soltanahmadi Y, Dadashpour M, Alipour S, Abolhasani S, Zarghami N . Synergistic Anticancer Effects of Silibinin and Chrysin in T47D Breast Cancer Cells. Asian Pac J Cancer Prev. 2017; 18(5):1283-1287. PMC: 5555536. DOI: 10.22034/APJCP.2017.18.5.1283. View

Peng H, Guerau-de-Arellano M, Mehta V, Yang Y, Huss D, Papenfuss T . Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem. 2012; 287(33):28017-26. PMC: 3431702. DOI: 10.1074/jbc.M112.383380. View

Waris G, Ahsan H . Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog. 2006; 5:14. PMC: 1479806. DOI: 10.1186/1477-3163-5-14. View

Paredes-Gonzalez X, Fuentes F, Jeffery S, Saw C, Shu L, Su Z . Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015; 36(7):440-51. DOI: 10.1002/bdd.1956. View

Mei D, Lv B, Chen B, Xiao S, Jiang J, Xie Y . All-trans retinoic acid suppresses malignant characteristics of CD133-positive thyroid cancer stem cells and induces apoptosis. PLoS One. 2017; 12(8):e0182835. PMC: 5560547. DOI: 10.1371/journal.pone.0182835. View

Park J, Huang S, Wu T, Foster N, Sinicrope F . Prognostic impact of Beclin 1, p62/sequestosome 1 and LC3 protein expression in colon carcinomas from patients receiving 5-fluorouracil as adjuvant chemotherapy. Cancer Biol Ther. 2012; 14(2):100-7. PMC: 3571991. DOI: 10.4161/cbt.22954. View

10.

Walsh J, Jenkins R, Wong M, Olayanju A, Powell H, Copple I . Identification and quantification of the basal and inducible Nrf2-dependent proteomes in mouse liver: biochemical, pharmacological and toxicological implications. J Proteomics. 2014; 108:171-87. PMC: 4115266. DOI: 10.1016/j.jprot.2014.05.007. View

11.

Yang D, Tan X, Lv Z, Liu B, Baiyun R, Lu J . Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity. Sci Rep. 2016; 6:37157. PMC: 5112569. DOI: 10.1038/srep37157. View

12.

Zeng W, Yan Y, Zhang F, Zhang C, Liang W . Chrysin promotes osteogenic differentiation via ERK/MAPK activation. Protein Cell. 2013; 4(7):539-47. PMC: 4875509. DOI: 10.1007/s13238-013-3003-3. View

13.

Shin D, Kim E, Lee J, Roh J . Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018; 129:454-462. DOI: 10.1016/j.freeradbiomed.2018.10.426. View

14.

Fisher C, Augustine L, Maher J, Nelson D, Slitt A, Klaassen C . Induction of drug-metabolizing enzymes by garlic and allyl sulfide compounds via activation of constitutive androstane receptor and nuclear factor E2-related factor 2. Drug Metab Dispos. 2007; 35(6):995-1000. DOI: 10.1124/dmd.106.014340. View

15.

Kim Y, Oh J, Kim M, Kang M, Park S, Han J . Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol. 2009; 220(4):446-51. DOI: 10.1002/path.2653. View

16.

Kalpana Deepa Priya D, Gayathri R, Sakthisekaran D . Role of sulforaphane in the anti-initiating mechanism of lung carcinogenesis in vivo by modulating the metabolic activation and detoxification of benzo(a)pyrene. Biomed Pharmacother. 2010; 65(1):9-16. DOI: 10.1016/j.biopha.2010.08.009. View

17.

Kunnumakkara A, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal B . Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res. 2008; 14(7):2128-36. DOI: 10.1158/1078-0432.CCR-07-4722. View

18.

Gao A, Ke Z, Wang J, Yang J, Chen S, Chen H . Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis. 2013; 34(8):1806-14. DOI: 10.1093/carcin/bgt108. View

19.

Roebuck B, Curphey T, Li Y, Baumgartner K, Bodreddigari S, Yan J . Evaluation of the cancer chemopreventive potency of dithiolethione analogs of oltipraz. Carcinogenesis. 2003; 24(12):1919-28. DOI: 10.1093/carcin/bgg173. View

20.

Bushue N, Wan Y . Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev. 2010; 62(13):1285-98. PMC: 2991380. DOI: 10.1016/j.addr.2010.07.003. View