Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

Abstract

Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

Keywords

Prostate cancer / androgen receptor / hormone therapy / endocrine resistance / oxidative stress / redox signaling / Nrf2 / Nrf2-activators

References

[1] Rawla P.Epidemiology of prostate cancer..World J Oncol2019;10:63-89 PMCID:PMC6497009

[2] Das H.Health care disparities in urologic oncology: a systematic review..Urology2020;136:9-18

[3] Chen R.Prostate cancer in Asia: a collaborative report..Asian J Urol2014;1:15-29 PMCID:PMC5832886

[4] Ha Chung B,Chiong E.The incidence, mortality, and risk factors of prostate cancer in Asian men..Prostate Int2019;7:1-8 PMCID:PMC6424686

[5] Labbé DP,Ebot EM.Role of diet in prostate cancer: the epigenetic link..Oncogene2015;34:4683-91 PMCID:PMC4476943

[6] Kgatle MM,Islam MM,Moorad R.Prostate cancer: epigenetic alterations, risk factors, and therapy..Prostate Cancer2016;2016:5653862 PMCID:PMC5116340

[7] Costa-Pinheiro P,Henrique R.Biomarkers and personalized risk stratification for patients with clinically localized prostate cancer..Expert Rev Anticancer Ther2014;14:1349-58

[8] Udensi UK.Oxidative stress in prostate hyperplasia and carcinogenesis..J Exp Clin Cancer Res2016;35:139 PMCID:PMC5017015

[9] Yu YD,Lee SE.Impact of body mass index on oncological outcomes of prostate cancer patients after radical prostatectomy..Sci Rep2018;8:11962 PMCID:PMC6086909

[10] Parikesit D,Umbas R.The impact of obesity towards prostate diseases..Prostate Int2016;4:1-6 PMCID:PMC4789344

[11] Harijith A,Natarajan V.Reactive oxygen species at the crossroads of inflammasome and inflammation..Front Physiol2014;5:352 PMCID:PMC4179323

[12] Khandrika L,Koul S,Koul HK.Oxidative stress in prostate cancer..Cancer Lett2009;282:125-36 PMCID:PMC2789743

[13] Landskron G,Thuwajit P,Hermoso MA.Chronic inflammation and cytokines in the tumor microenvironment..J Immunol Res2014;2014:149185 PMCID:PMC4036716

[14] Taniguchi K.NF-κB, inflammation, immunity and cancer: coming of age..Nat Rev Immunol2018;18:309-24

[15] Karantanos T,Thompson TC.Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches..Oncogene2013;32:5501-11 PMCID:PMC3908870

[16] Hoang DT,Kilari D,Nevalainen MT.Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: opportunities for therapeutic targeting from multiple angles..Oncotarget2017;8:3724-45 PMCID:PMC5356914

[17] Huang Y,Liang X.Molecular and cellular mechanisms of castration resistant prostate cancer..Oncol Lett2018;15:6063-76 PMCID:PMC5876469

[18] DiNatale A.The bone microenvironment in prostate cancer metastasis..Adv Exp Med Biol2019;1210:171-84

[19] Dong L,Xue W,Pienta KJ.Metastatic prostate cancer remains incurable, why?.Asian J Urol2019;6:26-41 PMCID:PMC6363601

[20] Hu R,Luo J.Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer..Expert Rev Endocrinol Metab2010;5:753-64 PMCID:PMC3035007

[21] Azevedo A,Teixeira AL.IL-6/IL-6R as a potential key signaling pathway in prostate cancer development..World J Clin Oncol2011;2:384-96 PMCID:PMC3235657

[22] Wardyn JD,Sanderson CM.Dissecting molecular crosstalk between Nrf2 and NF-κB response pathways..Biochem Soc Trans2015;43:621-6 PMCID:PMC4613495

[23] Wilson AH.The prostate gland: a review of its anatomy, pathology, and treatment..JAMA2014;312:562

[24] Litwin MS.The diagnosis and treatment of prostate cancer: a review..JAMA2017;317:2532-42

[25] Ilic D,Jung JH.Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis..BMJ2018;362:k3519 PMCID:PMC6283370

[26] Wu JT.Assay for prostate specific antigen (PSA): problems and possible solutions..J Clin Lab Anal1994;8:51-62

[27] Descotes JL.Diagnosis of prostate cancer..Asian J Urol2019;6:129-36 PMCID:PMC6488713

[28] Oranusi CK,Nwofor A.Diagnosis of prostate cancer with needle biopsy: should all cases be biopsied before treatment?.Niger J Clin Pract2012;15:48-50

[29] Chang AJ,Roach M3rd.High-risk prostate cancer-classification and therapy..Nat Rev Clin Oncol2014;11:308-23 PMCID:PMC4508854

[30] Grignon DJ.Prostate cancer reporting and staging: needle biopsy and radical prostatectomy specimens..Mod Pathol2018;31:S96-109

[31] Barakzai MA.Prostatic adenocarcinoma: a grading from gleason to the new grade-group system: a historical and critical review..Asian Pac J Cancer Prev2019;20:661-6 PMCID:PMC6825755

[32] Alford AV,Yadav KK,Tewari AK.The use of biomarkers in prostate cancer screening and treatment..Rev Urol2017;19:221-34 PMCID:PMC5811879

[33] Isbarn H,Carroll PR.Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks..Eur Urol2009;55:62-75 PMCID:PMC3090670

[34] Liu F,Zhou X.Effect of adjuvant hormone therapy in patients with prostate cancer: a meta-analysis of randomized controlled trials..Medicine (Baltimore)2018;97:e13145 PMCID:PMC6319968

[35] Xu X,Hu H,Taylor BD.Current opinion on the role of testosterone in the development of prostate cancer: a dynamic model..BMC Cancer2015;15:806 PMCID:PMC4623905

[36] Balk SP.Androgen receptor functions in prostate cancer development and progression..Asian J Androl2014;16:561-4 PMCID:PMC4104081

[37] Agoulnik IU.Androgen receptor action in hormone-dependent and recurrent prostate cancer..J Cell Biochem2006;99:362-72

[38] Perlmutter MA.Androgen deprivation therapy in the treatment of advanced prostate cancer..Rev Urol.2007;9 Suppl 1(Suppl 1):S3-8 PMCID:PMC1831539

[39] Kunath F,Rücker G.Non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer..Cochrane Database Syst Rev2014;6CD009266

[40] Kunath F,Pinart M.Early versus deferred standard androgen suppression therapy for advanced hormone-sensitive prostate cancer..Cochrane Database Syst Rev2019;6:CD003506 PMCID:PMC6564091

[41] Weiner AB,DeLancey JO,Auffenberg GB.Surgical versus medical castration for metastatic prostate cancer: use and overall survival in a national cohort..J Urol2020;203:933-9 PMCID:PMC7145732

[42] Lian F,Moran JD.The biology of castration-resistant prostate cancer..Curr Probl Cancer2015;39:17-28 PMCID:PMC4314372

[43] Scott LJ.Enzalutamide: a review in castration-resistant prostate cancer..Drugs2018;78:1913-24

[44] Iguchi T,Kato M,Yamasaki T.Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: study protocol for a multicenter randomized phase II trial (the OCUU-CRPC study)..BMC Cancer2019;19:339 PMCID:PMC6458677

[45] Evans CP,Keane T.The PREVAIL study: primary outcomes by site and extent of baseline disease for enzalutamide-treated men with chemotherapy-naïve metastatic castration-resistant prostate cancer..Eur Urol2016;70:675-83

[46] Lei JH,Wei Q.Androgen-deprivation therapy alone versus combined with radiation therapy or chemotherapy for nonlocalized prostate cancer: a systematic review and meta-analysis..Asian J Androl2016;18:102-7 PMCID:PMC4736336

[47] Buonerba C,Vitrone F.The influence of prednisone on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer..J Cancer2017;8:2663-8 PMCID:PMC5604196

[48] Den RB,Pieczonka C.Ra-223 treatment for bone metastases in castrate-resistant prostate cancer: practical management issues for patient selection..Am J Clin Oncol2019;42:399-406 PMCID:PMC6445613

[49] Marshall CH,DeWeese TL.Randomized phase II study of sipuleucel-T (SipT) with or without radium-223 (Ra223) in men with asymptomatic bone-metastatic castrate-resistant prostate cancer (mCRPC). Abstract 130. Presented at: ASCO Annual Genitourinary Cancers Symposium2020;February 13-15, 2020San Francisco, CA

[50] Davey RA.Androgen receptor structure, function and biology: from bench to bedside..Clin Biochem Rev2016;37:3-15 PMCID:PMC4810760

[51] Fujita K.Role of androgen receptor in prostate cancer: a review..World J Mens Health2019;37:288-95 PMCID:PMC6704300

[52] Nyquist MD.Interplay between genomic alterations and androgen receptor signaling during prostate cancer development and progression..Horm Cancer2013;4:61-9 PMCID:PMC3957092

[53] Augello MA,Knudsen KE.AR function in promoting metastatic prostate cancer..Cancer Metastasis Rev2014;33:399-411 PMCID:PMC4452946

[54] Eftekharzadeh B,Chiesa G.Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor..Nat Commun2019;10:3562 PMCID:PMC6687723

[55] Koochekpour S.Androgen receptor signaling and mutations in prostate cancer..Asian J Androl2010;12:639-57 PMCID:PMC3006239

[56] Sharma NL,Ramos-Montoya A.The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man..Cancer Cell2013;23:35-47

[57] Gritsina G,Yu J.Transcriptional repression by androgen receptor: roles in castration-resistant prostate cancer..Asian J Androl2019;21:215-23 PMCID:PMC6498738

[58] Wirth MP,Froehner M.Antiandrogens in the treatment of prostate cancer..Eur Urol2007;51:306-14

[59] Culig Z.Androgen receptor coactivators in regulation of growth and differentiation in prostate cancer..J Cell Physiol2016;231:270-4

[60] Muramatsu K,Sekine Y.Androgen receptor coactivator p120 subtype β is highly expressed in prostate cancer..Prostate Int2013;1:10-5 PMCID:PMC3821517

[61] Lopez SM,Zhang M.Nuclear receptor corepressor 1 expression and output declines with prostate cancer progression..Clin Cancer Res2016;22:3937-49 PMCID:PMC4970919

[62] Varenhorst E,Berglund A,Sandblom G.Predictors of early androgen deprivation treatment failure in prostate cancer with bone metastases..Cancer Med2016;5:407-14 PMCID:PMC4799954

[63] Jackson WC,Johnson SB.Duration of androgen deprivation therapy influences outcomes for patients receiving radiation therapy following radical prostatectomy..Eur Urol2016;69:50-7

[64] Chandrasekar T,Gao AC.Mechanisms of resistance in castration-resistant prostate cancer (CRPC)..Transl Androl Urol2015;4:365-80 PMCID:PMC4708226

[65] Song B,Zhao JC.Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression..J Clin Invest2019;129:569-82 PMCID:PMC6355239

[66] Wasmuth EV,Antar A,Chen Y.Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG..Proc Natl Acad Sci U S A2020;117:8584-92 PMCID:PMC7165421

[67] Zhang X,Sun S.Androgen receptor variants occur frequently in castration resistant prostate cancer metastases..PLoS One2011;6:e27970 PMCID:PMC3219707

[68] Wang Z,Liang Z,Wang C.The characteristics of androgen receptor splice variant 7 in the treatment of hormonal sensitive prostate cancer: a systematic review and meta-analysis..Cancer Cell Int2020;20:149 PMCID:PMC7201592

[69] Reddy V,Hwang C.Castration-resistant prostate cancer: androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death..PLoS One2019;14:e0211090 PMCID:PMC6513077

[70] Khurana N,Chandra PK.Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: advocating a potent pharmaceutical combination against castration-resistant prostate cancer..Oncol Rep2017;38:2774-86 PMCID:PMC5780030

[71] Khurana N,Kim H,Mondal D.Bardoxolone-methyl (CDDO-Me) suppresses androgen receptor and its splice-variant AR-V7 and enhances efficacy of enzalutamide in prostate cancer cells..Antioxidants (Basel)2020;9:68 PMCID:PMC7022272

[72] Hodgson MC,Agoulnik IU.Androgen receptor footprint on the way to prostate cancer progression..World J Urol2012;30:279-85 PMCID:PMC3360873

[73] Bastos DA.CTC-derived AR-V7 detection as a prognostic and predictive biomarker in advanced prostate cancer..Expert Rev Mol Diagn2018;18:155-63 PMCID:PMC6088794

[74] Bennett HL,Fleming JT.Does androgen-ablation therapy (AAT) associated autophagy have a pro-survival effect in LNCaP human prostate cancer cells?.BJU Int2013;111:672-82

[75] Das TP,Alatassi H,Damodaran C.Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer..Cell Death Dis2016;7:e2111 PMCID:PMC4849149

[76] Wolf P.Tumor-specific induction of the intrinsic apoptotic pathway-a new therapeutic option for advanced prostate cancer?.Front Oncol2019;9:590 PMCID:PMC6614431

[77] Wang X,Li R,Zhou L.Gene expression profiling analysis of castration-resistant prostate cancer..Med Sci Monit2015;21:205-12 PMCID:PMC4306671

[78] Josefsson A,Freyhult E,Welén K.Gene expression alterations during development of castration-resistant prostate cancer are detected in circulating tumor cells..Cancers (Basel)2019;12:39 PMCID:PMC7016678

[79] Schweizer MT.Persistent androgen receptor addiction in castration-resistant prostate cancer..J Hematol Oncol2015;8:128 PMCID:PMC4644296

[80] Chang KH,Kuri B.A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer..Cell2013;154:1074-84 PMCID:PMC3931012

[81] Kallio HML,Latonen L.Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases..Br J Cancer2018;119:347-56 PMCID:PMC6070921

[82] Sieuwerts AM,Kraan J.AR splice variants in circulating tumor cells of patients with castration-resistant prostate cancer: relation with outcome to cabazitaxel..Mol Oncol2019;13:1795-807 PMCID:PMC6670012

[83] Zhang T,Nissenblatt MJ.Androgen receptor splice variant, AR-V7, as a biomarker of resistance to androgen axis-targeted therapies in advanced prostate cancer..Clin Genitourin Cancer2020;18:1-10

[84] Khan T,Becker TM.The prospect of identifying resistance mechanisms for castrate-resistant prostate cancer using circulating tumor cells: is epithelial-to-mesenchymal transition a key player?.Prostate Cancer2020;2020:7938280 PMCID:PMC7149487

[85] Shiota M,Kashiwagi E.The role of nuclear receptors in prostate cancer..Cells2019;8:602 PMCID:PMC6627805

[86] Luo XH,Wang B.KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer..Endocr Relat Cancer2019;26:181-95

[87] Koike A,da Silva Bonacini AG.Thiol groups as a biomarker for the diagnosis and prognosis of prostate cancer..Sci Rep2020;10:9093 PMCID:PMC7272452

[88] Ghafar MA,Chen MW.Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells..Prostate2003;54:58-67

[89] Park SY,Gao AC.Hypoxia increases androgen receptor activity in prostate cancer cells..Cancer Res2006;66:5121-9

[90] Lee YG,Shin KJ.Androgen-induced expression of DRP1 regulates mitochondrial metabolic reprogramming in prostate cancer..Cancer Lett2020;471:72-87

[91] Nguyen DP,Tewari AK.Inflammation and prostate cancer: the role of interleukin 6 (IL-6)..BJU Int2014;113:986-92

[92] Sharma J,Harshman LC.Elevated IL-8, TNF-α, and MCP-1 in men with metastatic prostate cancer starting androgen-deprivation therapy (ADT) are associated with shorter time to castration-resistance and overall survival..Prostate2014;74:820-8

[93] Sciarra A,Salciccia S.Prognostic value of inflammation in prostate cancer progression and response to therapeutic: a critical review..J Inflamm (Lond)2016;13:35 PMCID:PMC5123292

[94] Yamada Y,Rii J.Prognostic value of an inflammatory index for patients with metastatic castration-resistant prostate cancer..Prostate2020;80:559-69

[95] Pu H,Kyprianou N.Aberrant TGF-β signaling drives castration-resistant prostate cancer in a male mouse model of prostate tumorigenesis..Endocrinology2017;158:1612-22 PMCID:PMC5460943

[96] Ottley EC,Gold EJ.Activin A regulates microRNAs and gene expression in LNCaP cells..Prostate2016;76:951-63

[97] Eiro N,Sacristán R.Stromal factors involved in human prostate cancer development, progression and castration resistance..J Cancer Res Clin Oncol2017;143:351-9

[98] Malinen M,Kaikkonen MU.Crosstalk between androgen and pro-inflammatory signaling remodels androgen receptor and NF-κB cistrome to reprogram the prostate cancer cell transcriptome..Nucleic Acids Res2017;45:619-30 PMCID:PMC5314794

[99] Erb HHH,Handle F.Assessment of STAT5 as a potential therapy target in enzalutamide-resistant prostate cancer..PLoS One2020;15:e0237248 PMCID:PMC7425943

[100] Sebastian T.Stop and go: anti-proliferative and mitogenic functions of the transcription factor C/EBPbeta..Cell Cycle2006;5:953-7

[101] Cao MQ,Cui W.Cross talk between oxidative stress and hypoxia via thioredoxin and HIF-2α drives metastasis of hepatocellular carcinoma..FASEB J2020;34:5892-905

[102] Auyeung KK.Angiogenesis and oxidative stress in metastatic tumor progression: pathogenesis and novel therapeutic approach of colon cancer..Curr Pharm Des2017;23:3952-61

[103] Culig Z.IL-6 causes multiple effects in androgen-sensitive and -insensitive prostate cancer cell lines..Expert Rev Endocrinol Metab2011;6:327-32

[104] Culig Z.Interleukin-6: a multifunctional targetable cytokine in human prostate cancer..Mol Cell Endocrinol2012;360:52-8 PMCID:PMC3409376

[105] Hudes G,Whang YE.A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer..Invest New Drugs2013;31:669-76

[106] Xu L,Shen M.Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels..Mol Oncol2018;12:269-86 PMCID:PMC5830627

[107] Tanaka T,Kishimoto T.IL-6 in inflammation, immunity, and disease..Cold Spring Harb Perspect Biol2014;6:a016295 PMCID:PMC4176007

[108] Kumari N,Das A.Role of interleukin-6 in cancer progression and therapeutic resistance..Tumour Biol2016;37:11553-72

[109] Zhang J,Stebler B,Keller ET.Orchiectomy increases bone marrow interleukin-6 levels in mice..Calcif Tissue Int1998;62:219-26

[110] Lee SO,Hou M,Gerber L.Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells..Clin Cancer Res2003;9:370-6

[111] Adler HL,Kattan MW,Scardino PT.Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma..J Urol1999;161:182-7

[112] Shariat SF,Kattan MW,Wheeler TM.Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis..Urology2001;58:1008-15

[113] Hobisch A,Hittmair A.Immunohistochemical localization of interleukin-6 and its receptor in benign, premalignant and malignant prostate tissue..J Pathol2000;191:239-44

[114] Luo Y.Hall of fame among pro-inflammatory cytokines: interleukin-6 gene and its transcriptional regulation mechanisms..Front Immunol2016;7:604 PMCID:PMC5165036

[115] Johnson DE,Grandis JR.Targeting the IL-6/JAK/STAT3 signalling axis in cancer..Nat Rev Clin Oncol2018;15:234-48 PMCID:PMC5858971

[116] Didion SP.Cellular and oxidative mechanisms associated with interleukin-6 signaling in the vasculature..Int J Mol Sci2017;18:2563 PMCID:PMC5751166

[117] Liu J,Chen J.The ROS-mediated activation of IL-6/STAT3 signaling pathway is involved in the 27-hydroxycholesterol-induced cellular senescence in nerve cells..Toxicol In Vitro2017;45:10-8

[118] Mauer J,Brüning JC.Versatile functions for IL-6 in metabolism and cancer..Trends Immunol2015;36:92-101

[119] Péant B,Le Page C.IκB-kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-β dependent activation of IL-6 gene expression..Oncotarget2017;8:14487-501 PMCID:PMC5362420

[120] Xiao W,Wang L,Zhang X.Co-operative functions between nuclear factors NFkappaB and CCAT/enhancer-binding protein-beta (C/EBP-beta) regulate the IL-6 promoter in autocrine human prostate cancer cells..Prostate2004;61:354-70

[121] Debelec-Butuner B,Varisli L.Inflammation-mediated abrogation of androgen signaling: an in vitro model of prostate cell inflammation..Mol Carcinog2014;53:85-97

[122] Mohanty SK,Pradhan D.STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer..Oncotarget2017;8:85997-6010 PMCID:PMC5689662

[123] Kim MH.Translationally regulated C/EBP beta isoform expression upregulates metastatic genes in hormone-independent prostate cancer cells..Prostate2008;68:1362-71

[124] Barakat DJ,Barberi T,Friedman AD.CCAAT/Enhancer binding protein β controls androgen-deprivation-induced senescence in prostate cancer cells..Oncogene2015;34:5912-22 PMCID:PMC4573387

[125] Maina PK,Liu Q.c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer..Oncotarget2016;7:75585-602 PMCID:PMC5342763

[126] Jiang C,Rasul A.Altholactone inhibits NF-κB and STAT3 activation and induces reactive oxygen species-mediated apoptosis in prostate cancer DU145 Cells..Molecules2017;22:240 PMCID:PMC6155856

[127] Nunes JJ,Yadav A,Ateeq B.Targeting NF-kappa B signaling by artesunate restores sensitivity of castrate-resistant prostate cancer cells to antiandrogens..Neoplasia2017;19:333-45 PMCID:PMC5358938

[128] Tam L,Traynor P,Bartlett JM.Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer..Br J Cancer2007;97:378-83 PMCID:PMC2360337

[129] Liu C,Lou W,Evans CP.Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells..Prostate2014;74:201-9 PMCID:PMC4437226

[130] Dorff TB,Pinski JK.Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer..Clin Cancer Res2010;16:3028-34 PMCID:PMC2898710

[131] Culig Z.Interleukin-6 and prostate cancer: current developments and unsolved questions..Mol Cell Endocrinol2018;462:25-30

[132] Burton GJ.Oxidative stress..Best Pract Res Clin Obstet Gynaecol2011;25:287-99 PMCID:PMC3101336

[133] Radi R.Oxygen radicals, nitric oxide, and peroxynitrite: redox pathways in molecular medicine..Proc Natl Acad Sci U S A2018;115:5839-48 PMCID:PMC6003358

[134] Schieber M.ROS function in redox signaling and oxidative stress..Curr Biol2014;24:R453-62 PMCID:PMC4055301

[135] Bryan S,Spicer D,Khaper N.Redox-inflammatory synergy in the metabolic syndrome..Can J Physiol Pharmacol2013;91:22-30

[136] Guang MHZ,Dunne LP.Targeting proteotoxic stress in cancer: a review of the role that protein quality control pathways play in oncogenesis..Cancers (Basel)2019;11:66 PMCID:PMC6356294

[137] Ashkavand Z,Ryan KC,Norman KR.Corrupted ER-mitochondrial calcium homeostasis promotes the collapse of proteostasis..Aging Cell2020;19:e13065 PMCID:PMC6974732

[138] Doghman-Bouguerra M.ER-mitochondria interactions: Both strength and weakness within cancer cells..Biochim Biophys Acta Mol Cell Res2019;1866:650-62

[139] Xia M,Jin K,Zeng Z.Communication between mitochondria and other organelles: a brand-new perspective on mitochondria in cancer..Cell Biosci2019;9:27 PMCID:PMC6425566

[140] Cockfield JA.Antioxidant defenses: a context-specific vulnerability of cancer cells..Cancers (Basel)2019;11:1208 PMCID:PMC6721511

[141] Acharya A,Chandhok D.Redox regulation in cancer: a double-edged sword with therapeutic potential..Oxid Med Cell Longev2010;3:23-34 PMCID:PMC2835886

[142] Arora H,Kuchakulla M.Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth..Proc Natl Acad Sci U S A.2018;115:11298-303 PMCID:PMC6217394

[143] Fontana F,Raimondi M.δ-Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells..Cell Prolif2019;52:e12576 PMCID:PMC6536411

[144] Lee S,Lee RT.Thioredoxin and thioredoxin target proteins: from molecular mechanisms to functional significance..Antioxid Redox Signal2013;18:1165-207 PMCID:PMC3579385

[145] Bansal A.Glutathione metabolism in cancer progression and treatment resistance..J Cell Biol2018;217:2291-8 PMCID:PMC6028537

[146] Meng Q,Liang C.Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3β/Snail signaling..Oncogene2018;37:5843-57

[147] Zalewska-Ziob M,Kasperczyk J.Activity of antioxidant enzymes in the tumor and adjacent noncancerous tissues of non-small-cell lung cancer..Oxid Med Cell Longev2019;2019:2901840 PMCID:PMC6875225

[148] Tonelli C,Tuveson DA.Transcriptional regulation by Nrf2..Antioxid Redox Signal2018;29:1727-45 PMCID:PMC6208165

[149] Sajadimajd S.Oxidative stress and cancer: the role of Nrf2..Curr Cancer Drug Targets2018;18:538-57

[150] Schultz MA,Datta A.Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells..PLoS One2014;9:e87204 PMCID:PMC3899380

[151] Schultz MA,Mondal D.The nrf1 and nrf2 balance in oxidative stress regulation and androgen signaling in prostate cancer cells..Cancers (Basel)2010;2:1354-78 PMCID:PMC3835133

[152] Sova M.Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review..Drug Des Devel Ther2018;12:3181-97 PMCID:PMC6161735

[153] Menegon S,Giordano S.The dual roles of NRF2 in cancer..Trends Mol Med2016;22:578-93

[154] Aggarwal V,Varol A.Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements..Biomolecules2019;9:735 PMCID:PMC6920770

[155] Perillo B,Pezone A.ROS in cancer therapy: the bright side of the moon..Exp Mol Med2020;52:192-203 PMCID:PMC7062874

[156] Zhang J,Vikash V.ROS and ROS-mediated cellular signaling..Oxid Med Cell Longev.2016;2016:4350965 PMCID:PMC4779832

[157] Shukla S,Shankar E.Oxidative stress and antioxidant status in high-risk prostate cancer subjects..Diagnostics (Basel)2020;10:126 PMCID:PMC7151307

[158] Shiota M,Naito S.Oxidative stress and androgen receptor signaling in the development and progression of castration-resistant prostate cancer..Free Radic Biol Med2011;51:1320-8

[159] Shiota M,Tada Y.Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression..Oncogene2010;29:237-50

[160] Shiota M,Itsumi M.Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress..Ann Oncol2017;28:569-75

[161] Pinthus JH,Trachtenberg J.Androgen induces adaptation to oxidative stress in prostate cancer: implications for treatment with radiation therapy..Neoplasia2007;9:68-80 PMCID:PMC1803036

[162] Shiota M,Naito S.Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer..Endocr Relat Cancer2012;19:R243-53

[163] Fajardo AM,Olguin SL,Rabinowitz I.Antioxidants abrogate alpha-tocopherylquinone-mediated down-regulation of the androgen receptor in androgen-responsive prostate cancer cells..PLoS One2016;11:e0151525 PMCID:PMC4795544

[164] Lu JP,Bryskin I.Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase..Prostate Cancer Prostatic Dis2010;13:39-46 PMCID:PMC2834342

[165] Höll M,Schäfer G.ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells..Mol Carcinog2016;55:27-39 PMCID:PMC4949723

[166] Wu QQ,Weng GB.Downregulated NOX4 underlies a novel inhibitory role of microRNA-137 in prostate cancer..J Cell Biochem2019;120:10215-27

[167] Schmid-Alliana A,Al-Sahlanee R,Scimeca JC.Understanding the progression of bone metastases to identify novel therapeutic targets..Int J Mol Sci2018;19:148 PMCID:PMC5796097

[168] Wang Y,Qiao Y.Wnt signaling drives prostate cancer bone metastatic tropism and invasion..Transl Oncol2020;13:100747 PMCID:PMC7109463

[169] Rana K,Zajac JD.Human androgen deficiency: insights gained from androgen receptor knockout mouse models..Asian J Androl2014;16:169-77 PMCID:PMC3955325

[170] Russell PK,Fam BC.The androgen receptor in bone marrow progenitor cells negatively regulates fat mass..J Endocrinol2018;237:15-27

[171] Bielecki B,Ghoumari AM.Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin..Proc Natl Acad Sci U S A2016;113:14829-34 PMCID:PMC5187716

[172] Abi-Ghanem C,Zuloaga KL.Androgens’ effects on cerebrovascular function in health and disease..Biol Sex Differ2020;11:35 PMCID:PMC7328272

[173] Vomund S,Parnham MJ,von Knethen A.Nrf2, the master regulator of anti-oxidative responses..Int J Mol Sci2017;18:2772 PMCID:PMC5751370

[174] Bellezza I,Minelli A.Nrf2-Keap1 signaling in oxidative and reductive stress..Biochim Biophys Acta Mol Cell Res2018;1865:721-33

[175] Satoh H,Taguchi K.Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung..Carcinogenesis2010;31:1833-43

[176] Khor TO,Prawan A.Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer..Cancer Prev Res (Phila)2008;1:187-91 PMCID:PMC3580177

[177] Xue D,Shi Y,Xu R.Nuclear transcription factor Nrf2 suppresses prostate cancer cells growth and migration through upregulating ferroportin..Oncotarget2016;7:78804-12 PMCID:PMC5346678

[178] Zhou Y,Zhao M,Lu Q.The bach family of transcription factors: a comprehensive review..Clin Rev Allergy Immunol2016;50:345-56

[179] Klotz LO,Prieto-Arroyo I,Steinbrenner H.Redox regulation of FoxO transcription factors..Redox Biol2015;6:51-72 PMCID:PMC4511623

[180] Robledinos-Antón N,Manda G.Activators and inhibitors of NRF2: a review of their potential for clinical development..Oxid Med Cell Longev2019;2019:9372182 PMCID:PMC6664516

[181] Cuadrado A,Wells G.Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases..Nat Rev Drug Discov2019;18:295-317

[182] Shin IS,Jeon CM.Diallyl-disulfide, an organosulfur compound of garlic, attenuates airway inflammation via activation of the Nrf-2/HO-1 pathway and NF-kappaB suppression..Food Chem Toxicol2013;62:506-13

[183] Macías-Pérez JR,Muñoz-Ortega MH.Curcumin and α/β-adrenergic antagonists cotreatment reverse liver cirrhosis in hamsters: participation of Nrf-2 and NF-κB..J Immunol Res2019;2019:3019794 PMCID:PMC6515016

[184] Impellizzeri D,Attley J.Targeting inflammation: new therapeutic approaches in chronic kidney disease (CKD)..Pharmacol Res2014;81:91-102

[185] Alam J,Touchard C,Choi AM.Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene..J Biol Chem1999;274:26071-8

[186] Gong P,Hu B,Alam J.Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite..Arch Biochem Biophys2002;405:265-74

[187] Dhakshinamoorthy S.c-Maf negatively regulates ARE-mediated detoxifying enzyme genes expression and anti-oxidant induction..Oncogene2002;21:5301-12

[188] Krajka-Kuźniak V,Baer-Dubowska W.The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment..Pharmacol Rep2017;69:393-402

[189] Raghunath A,Nagarajan R.Antioxidant response elements: discovery, classes, regulation and potential applications..Redox Biol2018;17:297-314 PMCID:PMC6007815

[190] Arlt A,Krebs S.Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity..Oncogene2013;32:4825-35

[191] Lee YJ,Lee SH.Nrf2 expression and apoptosis in quercetin-treated malignant mesothelioma cells..Mol Cells2015;38:416-25 PMCID:PMC4443283

[192] Feng T,Sun F.TXNDC9 regulates oxidative stress-induced androgen receptor signaling to promote prostate cancer progression..Oncogene2020;39:356-67

[193] Fajardo AM,Ji M.The curcumin analog ca27 down-regulates androgen receptor through an oxidative stress mediated mechanism in human prostate cancer cells..Prostate2012;72:612-25 PMCID:PMC3309160

[194] Liu GH,Shen X.NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK..Biochim Biophys Acta2008;1783:713-27

[195] Li W,Xu C.Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis..Biochem Pharmacol2008;76:1485-9 PMCID:PMC2610259

[196] Yu M,Liu Q.Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway..Cell Signal2011;23:883-92

[197] Jin R,Yu X.Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression..Oncogene2015;34:3700-10 PMCID:PMC4362792

[198] Qin DJ,Yang L.Hsp90 is a novel target molecule of CDDO-Me in inhibiting proliferation of ovarian cancer cells..PLoS One2015;10:e0132337 PMCID:PMC4489813

[199] Cuadrado A,Hassan A.Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach..Pharmacol Rev2018;70:348-83

[200] Magesh S,Hu L.Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents..Med Res Rev2012;32:687-726 PMCID:PMC3393814

[201] Hur W.Small molecule modulators of antioxidant response pathway..Curr Opin Chem Biol2011;15:162-73

[202] Jiménez-Osorio AS,Pedraza-Chaverri J.Natural Nrf2 activators in diabetes..Clin Chim Acta2015;448:182-92

[203] Houghton CA,Coombes JS.Sulforaphane and other nutrigenomic Nrf2 activators: can the Clinician’s expectation be matched by the reality?.Oxid Med Cell Longev2016;2016:7857186 PMCID:PMC4736808

[204] Zhou H,You Q.Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present)..Expert Opin Ther Pat2020;30:209-25

[205] Altmeyer PJ,Pawlak F.Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients..J Am Acad Dermatol1994;30:977-81

[206] Mrowietz U,Altmeyer P.Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German Multicentre Study..Br J Dermatol1998;138:456-60

[207] Mrowietz U,Loewe R.Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm((R)) - and placebo-controlled trial (BRIDGE)..Br J Dermatol2017;176:615-23

[208] Xu Z,Sun F,Dong S.Dimethyl fumarate for multiple sclerosis..Cochrane Database Syst Rev2015;4CD011076

[209] Linker RA,Ryan S.Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway..Brain2011;134:678-92

[210] Blewett MM,Zaro BW.Chemical proteomic map of dimethyl fumarate-sensitive cysteines in primary human T cells..Sci Signal2016;9:rs10 PMCID:PMC5068918

[211] Gillard GO,Anderson J.DMF, but not other fumarates, inhibits NF-κB activity in vitro in an Nrf2-independent manner..J Neuroimmunol2015;283:74-85

[212] Chen H,Krenz A.Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE..J Clin Invest2014;124:2188-92 PMCID:PMC4001545

[213] Tan SM,Stefanovic N.Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-associated atherosclerosis and improves diabetic kidney disease..Diabetes2014;63:3091-103

[214] Kastrati I,Calderon-Gierszal EL.Dimethyl fumarate inhibits the nuclear factor κB pathway in breast cancer cells by covalent modification of p65 protein..J Biol Chem2016;291:3639-47 PMCID:PMC4751401

[215] Johnson NM,Baxter VK.Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold..Cancer Prev Res (Phila)2014;7:658-65 PMCID:PMC4082474

[216] Nachliely M,Khalfin B.Dimethyl fumarate and vitamin D derivatives cooperatively enhance VDR and Nrf2 signaling in differentiating AML cells in vitro and inhibit leukemia progression in a xenograft mouse model..J Steroid Biochem Mol Biol2019;188:8-16

[217] Ahmadi-Beni R,Savar SM,Khoshnevisan A.Role of dimethyl fumarate in the treatment of glioblastoma multiforme: a review article..Iran J Neurol2019;18:127-33 PMCID:PMC6858600

[218] Kastrati I,Calderon-Gierszal EL.Dimethyl fumarate inhibits the nuclear factor κB pathway in breast cancer cells by covalent modification of p65 protein..J Biol Chem2016;291:3639-47 PMCID:PMC4751401

[219] Bennett Saidu NE,Mansuet AL.Dimethyl fumarate is highly cytotoxic in KRAS mutated cancer cells but spares non-tumorigenic cells..Oncotarget2018;9:9088-99 PMCID:PMC5823659

[220] Khurana N,Chandra PK.Sulforaphane increases the efficacy of anti-androgens by rapidly decreasing androgen receptor levels in prostate cancer cells..Int J Oncol2016;49:1609-19

[221] Nare B,Prichard RK.Mechanisms of inactivation of Schistosoma mansoni and mammalian glutathione S-transferase activity by the antischistosomal drug oltipraz..Biochem Pharmacol1992;43:1345-51

[222] Click RE.Anticancer activity and chemoprevention of xenobiotic organosulfurs in preclinical model systems..Oncol Discov2013;1:10.7243/2052-6199-1-4 PMCID:PMC4222532

[223] Shimozono R,Yoshizawa Y.Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model..Mol Pharmacol2013;84:62-70

[224] Yagishita Y,McCallum ML.Current Landscape of NRF2 Biomarkers in Clinical Trials..Antioxidants (Basel)2020;9:E716 PMCID:PMC7464243

[225] Qiu P,Li J.Overdose intake of curcumin initiates the unbalanced state of bodies..J Agric Food Chem2016;64:2765-71

[226] Chuengsamarn S,Phonrat B.Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a randomized controlled trial..J Nutr Biochem2014;25:144-50

[227] Na LX,Jiang S,Li Y.Curcuminoids target decreasing serum adipocyte-fatty acid binding protein levels in their glucose-lowering effect in patients with type 2 diabetes..Biomed Environ Sci2014;27:902-6

[228] Shishodia S,Aggarwal BB.Role of curcumin in cancer therapy..Curr Probl Cancer2007;31:243-305

[229] Woo JH,Choi YJ.Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt..Carcinogenesis2003;24:1199-208

[230] Lin SS,Yang JS.DNA damage and endoplasmic reticulum stress mediated curcumin-induced cell cycle arrest and apoptosis in human lung carcinoma A-549 cells through the activation caspases cascade- and mitochondrial-dependent pathway..Cancer Lett2008;272:77-90

[231] Basile V,Ferrari E.bis-Dehydroxy-curcumin triggers mitochondrial-associated cell death in human colon cancer cells through ER-stress induced autophagy..PLoS One2013;8:e53664 PMCID:PMC3543386

[232] Yin H,Xu Y.Synergistic antitumor efficiency of docetaxel and curcumin against lung cancer..Acta Biochim Biophys Sin (Shanghai)2012;44:147-53

[233] Abd Wahab NA,Abas F,Naidu R.Mechanism of anti-cancer activity of curcumin on androgen-dependent and androgen-independent prostate cancer..Nutrients2020;12:679 PMCID:PMC7146610

[234] Li W,Guo Y.Curcumin derivative epigenetically reactivates Nrf2 antioxidative stress signaling in mouse prostate cancer TRAMP C1 cells..Chem Res Toxicol2018;31:88-96 PMCID:PMC6295337

[235] Hong JH,Choi HY.Effect of curcumin on the interaction between androgen receptor and Wnt/β-catenin in LNCaP xenografts..Korean J Urol2015;56:656-65 PMCID:PMC4565901

[236] Mathur A,Liu X.Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells..PLoS One2014;9:e103109 PMCID:PMC4133210

[237] Nakamura K,Segawa T.Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines..Int J Oncol2002;21:825-30

[238] Fontana F,Marzagalli M,Limonta P.Natural compounds in prostate cancer prevention and treatment: mechanisms of action and molecular targets..Cells2020;9:460 PMCID:PMC7072821

[239] Dong S.Combination treatment of bicalutamide and curcumin has a strong therapeutic effect on androgen receptor-positive triple-negative breast cancers..Anticancer Drugs2020;31:359-67

[240] Pan MH,Lin JK.Biotransformation of curcumin through reduction and glucuronidation in mice..Drug Metab Dispos1999;27:486-94

[241] Lin TH,Niu Y.Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9(R) Lead to promotion versus suppression of prostate cancer metastasis..J Biol Chem2013;288:19359-69 PMCID:PMC3707641

[242] Hardwick J,Mehta M.Targeting cancer using curcumin encapsulated vesicular drug delivery systems..Curr Pharm Des2020;doi: 10.2174/1381612826666200728151610

[243] Yamashita S,Chuang KL.ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors..Neoplasia2012;14:74-83 PMCID:PMC3281944

[244] Abbaoui B,Riedl KM,Mortazavi A.Cruciferous vegetables, isothiocyanates, and bladder cancer prevention..Mol Nutr Food Res2018;62:e1800079 PMCID:PMC6196731

[245] Xu C,Chen C,Kong AN.Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells..Oncogene2005;24:4486-95

[246] Naujokat C.The “Big Five” phytochemicals targeting cancer stem cells: Curcumin, EGCG, Sulforaphane, resveratrol and genistein..Curr Med Chem2020;doi: 10.2174/0929867327666200228110738

[247] Houghton CA.Sulforaphane: Its “Coming of Age” as a clinically relevant nutraceutical in the prevention and treatment of chronic disease..Oxid Med Cell Longev2019;2019:2716870 PMCID:PMC6815645

[248] Jiang X,Zhang Z,Cai L.Protection by sulforaphane from type 1 diabetes-induced testicular apoptosis is associated with the up-regulation of Nrf2 expression and function..Toxicol Appl Pharmacol2014;279:198-210

[249] Artaud-Macari E,Brayer S.Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis..Antioxid Redox Signal2013;18:66-79

[250] Fois AG,Sotgia S.Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review..Respir Res2018;19:51 PMCID:PMC5872514

[251] Jiang T,Zheng H.Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response..Kidney Int2014;85:333-43 PMCID:PMC3992978

[252] Singh KB,Alumkal JJ.Reversal of the Warburg phenomenon in chemoprevention of prostate cancer by sulforaphane..Carcinogenesis2019;40:1545-56 PMCID:PMC7175465

[253] Ullah MF.Sulforaphane (SFN): an isothiocyanate in a cancer chemoprevention paradigm..Medicines (Basel)2015;2:141-56 PMCID:PMC5456215

[254] Kamal MM,Lin CN.Sulforaphane as an anticancer molecule: mechanisms of action, synergistic effects, enhancement of drug safety, and delivery systems..Arch Pharm Res2020;43:371-84

[255] Zhang C,Khor TO,Kong AN.Sulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation..Biochem Pharmacol2013;85:1398-404 PMCID:PMC4123317

[256] Beaver LM,Clarke JD.Broccoli sprouts delay prostate cancer formation and decrease prostate cancer severity with a concurrent decrease in HDAC3 protein expression in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice..Curr Dev Nutr2017;2:nzy002 PMCID:PMC6041877

[257] Keum YS,Lin W.Pharmacokinetics and pharmacodynamics of broccoli sprouts on the suppression of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: implication of induction of Nrf2, HO-1 and apoptosis and the suppression of Akt-dependent kinase pathway..Pharm Res2009;26:2324-31

[258] Farkhondeh T,Pourbagher-Shahri AM,Samarghandian S.The therapeutic effect of resveratrol: focusing on the Nrf2 signaling pathway..Biomed Pharmacother2020;127:110234

[259] Berman AY,Wiesenfeld MY.The therapeutic potential of resveratrol: a review of clinical trials..NPJ Precis Oncol2017;1:35 PMCID:PMC5630227

[260] Xia N,Förstermann U.Antioxidant effects of resveratrol in the cardiovascular system..Br J Pharmacol2017;174:1633-46 PMCID:PMC5446570

[261] Ungvari Z,Feher A.Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2..Am J Physiol Heart Circ Physiol2010;299:H18-24 PMCID:PMC2904129

[262] Ghanim H,Korzeniewski K.A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal..J Clin Endocrinol Metab2011;96:1409-14 PMCID:PMC3085195

[263] Ávila-Gálvez MÁ,Espín JC.Dietary phenolics against breast cancer. A critical evidence-based review and future perspectives..Int J Mol Sci2020;21:E5718 PMCID:PMC7461055

[264] Ding S,Fang J.The protective effect of polyphenols for colorectal cancer..Front Immunol2020;11:1407 PMCID:PMC7366338

[265] Kumar A,Levenson AS.Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer..Ann N Y Acad Sci2017;1403:15-26

[266] Wilson S,Tong D.Resveratrol enhances polyubiquitination-mediated ARV7 degradation in prostate cancer cells..Oncotarget2017;8:54683-93 PMCID:PMC5589613

[267] De Amicis F,Montalto FI,Sirianni R.Steroid receptor signallings as targets for resveratrol actions in breast and prostate cancer..Int J Mol Sci2019;20:1087 PMCID:PMC6429419

[268] Shanmugam MK,Kumar AP,Sethi G.Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: potential role in prevention and therapy of cancer..Cancer Lett2012;320:158-70

[269] Pergola PE,Toto RD.Bardoxolone methyl and kidney function in CKD with type 2 diabetes..N Engl J Med2011;365:327-36

[270] Chin MP,Bakris GL.Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl..J Card Fail2014;20:953-8

[271] Wang YY,Zhe H,Zhou SF.Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties..Drug Des Devel Ther2014;8:2075-88 PMCID:PMC4211867

[272] Baigent C.Should we increase GFR with Bardoxolone in Alport syndrome?.J Am Soc Nephrol2018;29:357-9 PMCID:PMC5791073

[273] Wang YY,Zhao R.Preclinical evidences toward the use of triterpenoid CDDO-Me for solid cancer prevention and treatment..Mol Cancer2014;13:30 PMCID:PMC3940295

[274] Deeb D,Jiang H,Gautam SC.Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro-survival Akt and mTOR..Prostate2009;69:851-60 PMCID:PMC3865612

[275] Kim EH,Sporn MB.CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice..Cancer Prev Res (Phila)2012;5:89-97 PMCID:PMC3252488

[276] Gao X,Deeb D.Synthetic oleanane triterpenoid, CDDO-Me, induces apoptosis in ovarian cancer cells by inhibiting prosurvival AKT/NF-κB/mTOR signaling..Anticancer Res2011;31:3673-81 PMCID:PMC3711099

[277] Liby K,Williams CR.The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice..Cancer Res2007;67:2414-9

[278] Liby KT,Risingsong R.Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer..Cancer Prev Res (Phila)2010;3:1427-34 PMCID:PMC2988079

[279] Ryu K,Choy E.Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway..BMC Cancer2010;10:187 PMCID:PMC2874784

[280] Dinkova-Kostova AT,Stephenson KK.Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress..Proc Natl Acad Sci U S A2005;102:4584-9 PMCID:PMC555528

[281] Hong DS,Supko JG.A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas..Clin Cancer Res2012;18:3396-406 PMCID:PMC4494099

[282] Gao X,Liu Y.Prevention of prostate cancer with oleanane synthetic triterpenoid CDDO-Me in the TRAMP mouse model of prostate cancer..Cancers (Basel)2011;3:3353-69 PMCID:PMC3180910

[283] Liu Y,Deeb D,Gautam SC.Telomerase reverse transcriptase (TERT) is a therapeutic target of oleanane triterpenoid CDDO-Me in prostate cancer..Molecules2012;17:14795-809 PMCID:PMC3607816

[284] Madsen KL,Cohen BH.Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy: MOTOR trial..Neurology2020;94:e687-98 PMCID:PMC7176297

[285] Probst BL,McCauley L.RTA 408, A novel synthetic triterpenoid with broad anticancer and anti-inflammatory activity..PLoS One2015;10:e0122942 PMCID:PMC4405374

[286] Abeti R,Esteras N.Novel Nrf2-inducer prevents mitochondrial defects and oxidative stress in Friedreich’s ataxia models..Front Cell Neurosci2018;12:188 PMCID:PMC6056642

[287] Rabbani PS,Waqas B.Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds..Diabetes Res Clin Pract2018;139:11-23

[288] Sun X,Hu B.The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling..Redox Biol2020;28:101309 PMCID:PMC6728880

[289] Reisman SA,Lee CI.Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis..J Biochem Mol Toxicol2020;e22526:

[290] Rodriguez-Duarte J,Galliussi G.Electrophilic nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses..Sci Rep2018;8:12784 PMCID:PMC6109136

[291] Schopfer FJ,Jorkasky DK.Nitro-fatty acids: new drug candidates for chronic inflammatory and fibrotic diseases..Nitric Oxide2018;79:31-7 PMCID:PMC6280193

[292] Zhang P,Yegnasubramanian S.Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth..Mol Cancer The2010;9:336-46 PMCID:PMC2821808

[293] Ciamporcero E,Pizzimenti S.Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer..Free Radic Biol Med2018;115:447-57

[294] Ischia J,Gleave M.The promise of heat shock protein inhibitors in the treatment of castration resistant prostate cancer..Curr Opin Urol2013;23:194-200

[295] Azad AA,Gleave ME.Targeting heat shock proteins in metastatic castration-resistant prostate cancer..Nat Rev Urol2015;12:26-36

[296] Fernandez-Salas E,Chinnaiyan AM.Role of BET proteins in castration-resistant prostate cancer..Drug Discov Today Technol2016;19:29-38

[297] Urbanucci A.Bromodomain-containing proteins in prostate cancer..Mol Cell Endocrinol2018;462:31-40