Nordihydroguaiaretic Acid: From Herbal Medicine to Clinical Development for Cancer and Chronic Diseases

Overview

Journal Front Pharmacol

Date 2020 Mar 19

PMID 32184727

Citations 21

Authors

Gina Manda

Ana I Rojo

Elena Martinez-Klimova

Jose Pedraza-Chaverri

Antonio Cuadrado

Affiliations

Soon will be listed here.

Abstract

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from , the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. NDGA presents two catechol rings that confer a very potent antioxidant activity by scavenging oxygen free radicals and this may explain part of its therapeutic action. Additional effects include inhibition of lipoxygenases (LOXs) and activation of signaling pathways that impinge on the transcription factor Nuclear Factor Erythroid 2-related Factor (NRF2). On the other hand, the oxidation of the catechols to the corresponding quinones my elicit alterations in proteins and DNA that raise safety concerns. This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer.

Citing Articles

Synergistic involvement of the NZF domains of the LUBAC accessory subunits HOIL-1L and SHARPIN in the regulation of LUBAC function.

Toda Y, Fujita H, Mino K, Koyama T, Matsuoka S, Kaizuka T Cell Death Dis. 2024; 15(11):813.

PMID: 39528476 PMC: 11555115. DOI: 10.1038/s41419-024-07199-z.

Impact of Nordihydroguaiaretic Acid on Proliferation, Energy Metabolism, and Chemosensitization in Non-Small-Cell Lung Cancer (NSCLC) Cell Lines.

Chipon C, Riffo P, Ojeda L, Salas M, Burgos R, Ehrenfeld P Int J Mol Sci. 2024; 25(21).

PMID: 39519155 PMC: 11546251. DOI: 10.3390/ijms252111601.

Investigation of small molecules disrupting dengue virus assembly by inhibiting capsid protein and blocking RNA encapsulation.

Panday H, Jha A, Dwivedi V Mol Divers. 2024; .

PMID: 39304568 DOI: 10.1007/s11030-024-10980-z.

and Its Pinostrobin for Atopic Dermatitis: Dual 5-Lipoxygenase and Cyclooxygenase-2 Inhibitor and Its Mechanistic Study through Steady-State Kinetics and Molecular Modeling.

Liana D, Eurtivong C, Phanumartwiwath A Antioxidants (Basel). 2024; 13(1).

PMID: 38247498 PMC: 10812521. DOI: 10.3390/antiox13010074.

Nordihydroguaiaretic Acid Affects Undifferentiated and Differentiated Neuroblastoma Cells Differently through Mechanisms that Impact on Cell Viability.

Ferrera P, De la Fuente-Munoz C, Arias C CNS Neurol Disord Drug Targets. 2023; 23(9):1167-1175.

PMID: 38151851 DOI: 10.2174/0118715273268471231013135114.

References

Satoh T, McKercher S, Lipton S . Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs. Free Radic Biol Med. 2013; 65:645-657. PMC: 3859717. DOI: 10.1016/j.freeradbiomed.2013.07.022. View

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

Cuadrado A, Manda G, Hassan A, Alcaraz M, Barbas C, Daiber A . Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach. Pharmacol Rev. 2018; 70(2):348-383. DOI: 10.1124/pr.117.014753. View

Moss M, Varvel N, Nichols M, Reed D, Rosenberry T . Nordihydroguaiaretic acid does not disaggregate beta-amyloid(1-40) protofibrils but does inhibit growth arising from direct protofibril association. Mol Pharmacol. 2004; 66(3):592-600. DOI: 10.1124/mol.66.3.. View

Jeon S, Ji K, You H, Kim J, Jou I, Joe E . Nordihydroguaiaretic acid inhibits IFN-gamma-induced STAT tyrosine phosphorylation in rat brain astrocytes. Biochem Biophys Res Commun. 2005; 328(2):595-600. DOI: 10.1016/j.bbrc.2005.01.025. View

Smith A, Feddersen R, GARDNER Jr K, Davis Jr C . Cystic renal cell carcinoma and acquired renal cystic disease associated with consumption of chaparral tea: a case report. J Urol. 1994; 152(6 Pt 1):2089-91. DOI: 10.1016/s0022-5347(17)32317-0. View

Shaposhnikova V, Kublik L, Narimanov A, Levitman M, Orlova O, Kudriavtsev A . [Growth inhibition and induction of tumor cell death by phospholipase A2 and lipoxygenase inhibitors]. Izv Akad Nauk Ser Biol. 2001; (2):249-52. View

Katsuoka F, Yamamoto M . Small Maf proteins (MafF, MafG, MafK): History, structure and function. Gene. 2016; 586(2):197-205. PMC: 4911266. DOI: 10.1016/j.gene.2016.03.058. View

Rieckmann P, Traboulsee A, Devonshire V, Oger J . Escalating immunotherapy of multiple sclerosis. Ther Adv Neurol Disord. 2010; 1(3):181-92. PMC: 3002550. DOI: 10.1177/1756285608098359. View

10.

Lee D, Kwak I, Lee S, Song S, Seong E, Chul Chung H . Effects of celecoxib and nordihydroguaiaretic acid on puromycin aminonucleoside-induced nephrosis in the rat. J Korean Med Sci. 2009; 24 Suppl:S183-8. PMC: 2633184. DOI: 10.3346/jkms.2009.24.S1.S183. View

11.

Lambert J, Zhao D, Meyers R, Kuester R, Timmermann B, Dorr R . Nordihydroguaiaretic acid: hepatotoxicity and detoxification in the mouse. Toxicon. 2002; 40(12):1701-8. DOI: 10.1016/s0041-0101(02)00203-9. View

12.

Li X, Fan S, Pan X, Xiaokaiti Y, Duan J, Shi Y . Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1. Oncotarget. 2016; 7(52):86225-86238. PMC: 5349909. DOI: 10.18632/oncotarget.13368. View

13.

. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016; 12(4):459-509. DOI: 10.1016/j.jalz.2016.03.001. View

14.

Singh M, Bittner S, Li Y, Bittner A, Han L, Cortez Y . Anti-hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats. Br J Pharmacol. 2018; 176(3):369-385. PMC: 6329620. DOI: 10.1111/bph.14528. View

15.

Mundhe N, Kumar P, Arora I, Ahmed S, Lahkar M . Differential effect of NDGA on cisplatin-induced nephrotoxicity in Spargue-Dawley rats. Immunopharmacol Immunotoxicol. 2019; 41(1):68-75. DOI: 10.1080/08923973.2018.1547741. View

16.

Cuadrado A, Rojo A, Wells G, Hayes J, Cousin S, Rumsey W . Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019; 18(4):295-317. DOI: 10.1038/s41573-018-0008-x. View

17.

Evan A, GARDNER Jr K . Nephron obstruction in nordihydroguaiaretic acid-induced renal cystic disease. Kidney Int. 1979; 15(1):7-19. DOI: 10.1038/ki.1979.2. View

18.

Arteaga S, Andrade-Cetto A, Cardenas R . Larrea tridentata (Creosote bush), an abundant plant of Mexican and US-American deserts and its metabolite nordihydroguaiaretic acid. J Ethnopharmacol. 2005; 98(3):231-9. DOI: 10.1016/j.jep.2005.02.002. View

19.

Martin D, Salinas M, Fujita N, Tsuruo T, Cuadrado A . Ceramide and reactive oxygen species generated by H2O2 induce caspase-3-independent degradation of Akt/protein kinase B. J Biol Chem. 2002; 277(45):42943-52. DOI: 10.1074/jbc.M201070200. View

20.

Arvanitakis Z, Shah R, Bennett D . Diagnosis and Management of Dementia: Review. JAMA. 2019; 322(16):1589-1599. PMC: 7462122. DOI: 10.1001/jama.2019.4782. View