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Friend or Foe: Xenobiotic Activation of Nrf2 in Disease Control and Cardioprotection

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Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that governs a highly conserved pathway central to the protection of cells against various oxidative stresses. However, the biological impact of xenobiotic intervention of Nrf2 in physiological and pathophysiological conditions remains debatable. Activation of Nrf2 in cancer cells has been shown to elevate drug resistance and increase cell survival and proliferation, while inhibition of Nrf2 sensitizes cancer cells to drug treatment. On the other hand, activation of Nrf2 in normal healthy cells has been explored as a rather successful strategy for cancer chemoprevention. Selective activation of Nrf2 in off-target cells has recently been investigated as an approach for protecting off-target tissues from untoward drug toxicity. Specifically, induction of antioxidant response element genes via Nrf2 activation in cardiac cells is being explored as a means to limit the well-documented cardiotoxicity accompanied by cancer treatment with commonly prescribed anthracycline drugs. In addition to cancers, Nrf2 has been implicated in many other diseases including Alzheimer’s and Parkinson’s Diseases, diabetes, and cardiovascular disease. In this review, we discuss the roles of Nrf2 and its downstream target genes in the treatment of various diseases, and its recently explored potential for increasing the benefit: risk ratio of commonly utilized cancer treatments.

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Abbreviations

AD:

Alzheimer’s Disease

AKR:

Aldo-keto reductase

ALA:

Alpha linolenic acid

AML:

Acute myeloid leukemia

ARE:

Antioxidant response element

ATO:

Arsenic trioxide

BCRP:

Breast cancer resistance protein

bZIP:

Basic leucine zipper

CAT:

Catalase

CDDO-Im:

1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole

CDDO-Me:

Bardoxolone methyl

CKD:

Chronic kidney disease

DCAC:

Dichloroacetyl chloride

DIM:

3,3’diindolymethane

DMF:

Dimethyl fumarate

DOX:

Doxorubicin

ERK:

Extracellular signal regulated kinase pathway

GCLC:

Glutamate-cysteine ligase catalytic subunit

GSK3:

Glycogen synthase 3

GPx:

Glutathione peroxidase

GSH:

Glutathione

HO-1:

Heme oxygenase 1

Keap1:

Kelch like-ECH-associated protein 1

LBVAD:

Lewy body variant of Alzheimer’s Disease

LRRK2:

Leucine-rich repeat kinase 2

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MRP:

Multidrug resistance-associated protein

NAFLD:

Nonalcoholic fatty liver disease

NQO1:

NAD(P)H quinone dehydrogenase

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

PD:

Parkinson’s Disease

PKC:

Protein kinase c

ROS:

Reactive oxygen species

scRNA:

Scrambled RNA

SFN:

Sulforaphane

shRNA:

Short hairpin RNA

siRNA:

Small interfering RNA

SOD:

Superoxide dismutase

SQSTM1:

Sequestosome 1

tBHQ:

Tert-butylhydroquinolone

TCE:

Trichloroethylene

TUDCA:

Tauroursodeoxycholic acid

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ACKNOWLEDGMENTS AND DISCLOSURES

The study was partly supported by the Food and Drug Administration (FDA) Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI) initiative (1U01FD005946). The authors disclose that there is no potential conflict of interest. The contents do not represent the views of the FDA.

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  1. William D. Hedrich

    Present address: Bristol-Myers Squibb Company, Pharmaceutical Candidate Optimization, Metabolism and Pharmacokinetics, Rt. 206 and Province Line Road, Princeton, New Jersey, 08543, USA

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  1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA

    William D. Hedrich & Hongbing Wang

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Hedrich, W.D., Wang, H. Friend or Foe: Xenobiotic Activation of Nrf2 in Disease Control and Cardioprotection. Pharm Res 38, 213–241 (2021). https://doi.org/10.1007/s11095-021-02997-y

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