Nrf2 signaling pathway in cisplatin chemotherapy: Potential involvement in organ protection and chemoresistance. (May 2021)

• Record Type: Journal Article
• Authors: Mirzaei, Sepideh; Mohammadi, Aliasghar Tabatabaei; Gholami, Mohammad Hossein; Hashemi, Farid; Zarrabi, Ali; Zabolian, Amirhossein; Hushmandi, Kiavash; Makvandi, Pooyan; Samec, Marek; Liskova, Alena; Kubatka, Peter; Nabavi, Noushin; Aref, Amir Reza; Ashrafizadeh, Milad; Khan, Haroon; Najafi, Masoud
• Is Part Of: Pharmacological research. Volume 167(2021)
• Publication Date: 2021-05
• Subjects: Nrf2 nuclear factor erythroid 2-related factor 2 -- ARE antioxidant response element -- ROS reactive oxygen species -- HO-1 heme oxygenase-1 -- NQO1 NAD(p)H quinone oxidoreductase 1 -- SLC7A11 solute carrier family 7 membrane 11 -- GPX glutathione peroxidase -- CP cisplatin -- CAT catalase -- SOD superoxide dismutase -- PI3K phosphoinositide 3-kinase -- Akt protein kinase-B -- TR1 thioredoxin reductase 1 -- 5-FU 5-fluorouracil -- PAQR4 Progestion and AdipoQ Receptor 4 -- lncRNA long non-coding RNA -- UCA1 urothelial cancer associated 1 -- NER nucleotide excision repair -- BER base excision repair -- GLUT3 glucose transporter 3 -- GSK-3b glycogen synthase kinase-3 beta -- Aila Ailanthone -- miRNA microRNA -- Hsp90 heat shock protein 90 -- EGFR epidermal growth factor receptor -- UA ursolic acid -- ER endoplasmic reticulum -- CHOP CCAAT-enhancer-binding protein homologous protein -- HIF-1a hypoxia inducible factor-1a -- GPx4 glutathione peroxidase 4 -- STAT3 signal transducer and activator of transcription 3 -- Scrib scribble -- PD-L1 programmed death-ligand 1 -- PAR1 pseudoautosomal region 1 -- ATP ABC-binding cassette -- TMD transmembrane domain -- NBD nucleotide-binding domain -- MAPK mitogen-activated protein kinase -- MKP-1 MAPK phosphatase 1 -- Cul3 cullin3 -- ATGs autophagy-related genes -- siRNA small interfering RNA -- NES NRF2 nuclear export signal -- JNK c-Jun N-terminal kinase -- ncRNAs non-coding RNAs -- ceRNA competing endogenous RNA -- TUG1 taurine upregulated gene 1 -- 3/-UTR 3/-untranslated region -- MDA malondialdehyde -- PIC piceatannol -- Res resveratrol -- BBB blood-brain barrier -- EGCG epigallocatechin gallate -- TMP tetramethylpyrazine -- ALS amyotrophic lateral sclerosis -- AKI acute kidney injury -- mTOR mammalian target of rapamycin -- SIRTs sirtuins -- LC-3 light chain-3; Nrf2 -- Cisplatin -- Chemoresistance -- Chemoprotection -- ROS -- Oxidative stress; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105575
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor and its induction is of significant importance for protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) stimulate Nrf2 signaling, enhancing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. These enzymes are associated with retarding oxidative stress. On the other hand, Nrf2 activation in cancer cells is responsible for the development of chemoresistance due to disrupting oxidative mediated-cell death by reducing ROS levels. Cisplatin (CP), cis-diamminedichloroplatinum(II), is a potent anti-tumor agent extensively used in cancer therapy, but its frequent application leads to the development of chemoresistance as well. In the present study, association of Nrf2 signaling with chemoresistance to CP and protection against its deleterious effects is discussed. Anti-tumor compounds, mainly phytochemicals, retard chemoresistance by suppressing Nrf2 signaling. Upstream mediators such as microRNAs can regulate Nrf2 expression during CP chemotherapy regimens. Protection against side effects of CP is mediated via activating Nrf2 signaling and its downstream targets activating antioxidant defense system. Protective agents that activate Nrf2 signaling, can ameliorate CP-mediated ototoxicity, nephrotoxicity and neurotoxicity. Reducing ROS levels and preventing cell death are the most important factors involved in alleviating CP toxicity upon Nrf2 activation. As pre-clinical experiments advocate the role of Nrf2 in chemoprotection and CP resistance, translating these findings to the clinic can provide a significant progress in treatment of cancer patients. Graphical Abstract: ga1 Highlights: Nrf2 regulates response of cells to oxidative stress by enhancing activities of antioxidant enzymes. Nrf2 activation can protect cells against side effects of chemotherapeutic agents. Cisplatin (CP) inhibits cancer progresion via inducing DNA damage and enhancing reactive oxygen species (ROS) levels. Nrf2 activation prevents cell death and cytotoxicity of CP in cancer cells via ameliorating oxidative stress and ROS levels. Nrf2 activation reduces ROS levels to alleviate CP-mediated nephrotoxicity, neurotoxicity and ototoxicity.