Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Medicinal Research Reviews, Journal Year: 2023, Volume and Issue: 43(3), P. 614 - 682

Published: Jan. 19, 2023

Abstract Ferroptosis is an iron‐dependent cell death program that characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions structural features of ferroptosis‐inducing compounds might therefore open door efficient pharmacological strategies against aggressive, metastatic, therapy‐resistant cancer. We here summarize mechanisms requirements small molecules target central players ferroptosis. Focus placed on (i) glutathione peroxidase (GPX) 4, only GPX isoenzyme detoxifies complex membrane‐bound hydroperoxides, (ii) cystine/glutamate antiporter system X c − for regeneration, (iii) redox‐protective transcription factor nuclear erythroid 2‐related (NRF2), (iv) GPX4 repression combination with induced heme degradation via oxygenase‐1. deduce common ferroptotic activity highlight challenges development. Moreover, we critically discuss potential natural products lead structures provide comprehensive overview structurally diverse biogenic bioinspired trigger iron oxidation, inhibition thioredoxin/thioredoxin reductase or less defined modes action.

Language: Английский

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Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(3), P. 579 - 615

Published: Jan. 24, 2024

Abstract This article provides an overview of the background knowledge ferroptosis in nervous system, as well key role nuclear factor E2-related 2 (Nrf2) regulating ferroptosis. The takes Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS) starting point to explore close association between Nrf2 ferroptosis, which is clear significant importance for understanding mechanism neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links pathogenesis NDs. As progresses, damage antioxidant excessive OS, altered expression levels, especially inhibition by lipid peroxidation inhibitors adaptive enhancement signaling, demonstrate potential clinical significance detecting identifying targeted therapy neuronal loss mitochondrial dysfunction. These findings provide new insights possibilities treatment prevention

Language: Английский

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Natural products as non-covalent and covalent modulators of the KEAP1/NRF2 pathway exerting antioxidant effects

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 270, P. 116355 - 116355

Published: March 26, 2024

Language: Английский

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Potential Applications of NRF2 Modulators in Cancer Therapy

Antioxidants, Journal Year: 2020, Volume and Issue: 9(3), P. 193 - 193

Published: Feb. 25, 2020

The nuclear factor erythroid 2-related 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, NRF2 transcription has been implicated physiopathology several human diseases, including cancer. In this respect, accumulating evidence indicates that can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on specific biological context its activation. Thus, better understanding mechanisms control functions most appropriate activation is prerequisite for development effective therapeutic strategies based modulation. line principle, controlled might reduce risk cancer initiation normal by scavenging reactive-oxygen species (ROS) preventing genomic instability through decreased DNA damage. contrast however, already transformed with constitutive prolonged signaling represent major clinical hurdle exhibit aggressive phenotype characterized therapy resistance unfavorable prognosis, requiring use inhibitors. review, we will focus dual roles NRF2-KEAP1 promotion inhibition, describing potential context-specific modulation NRF2.

Language: Английский

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Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management?

Antioxidants, Journal Year: 2020, Volume and Issue: 9(10), P. 973 - 973

Published: Oct. 11, 2020

The nuclear factor erythroid 2-related 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cell signaling mechanism in maintaining redox homeostasis humans. role of dietary flavonoids activating Nrf2/ARE relation to cancer chemoprevention or promotion not well established. Here we summarize the dual effects and with respect regulation pathway, while underlying possible cellular mechanisms. Luteolin, apigenin, quercetin, myricetin, rutin, naringenin, epicatechin, genistein activate both normal cells. hormetic effect has been observed due their antioxidant prooxidant activity, depending on concentrations. Reported vitro vivo investigations suggest that activation by either endogenous exogenous stimuli under physiological conditions contributes homeostasis, which may provide a for chemoprevention. However, some flavonoids, such as luteolin, genistein, daidzein, at low concentrations (1.5 20 µM) facilitate growth proliferation vitro. Paradoxically, including chrysin, inhibit Therefore, even though play major chemoprevention, inducement growth, pathophysiology patients appropriate experimental animal models should be investigated systematically.

Language: Английский

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Melatonin as a potential modulator of Nrf2

Fundamental and Clinical Pharmacology, Journal Year: 2019, Volume and Issue: 34(1), P. 11 - 19

Published: July 8, 2019

Abstract Nuclear factor erythroid 2‐related 2 (Nrf2) is considered as the sensor of oxidative stress, and main aim this signaling pathway to maintain physiological condition by induction redox balance. Also, exerts anti‐inflammatory effects via antioxidant response element. Oxidative stress a key in variety pathological conditions high level associated with damages lipids, proteins, genetic material, cell membrane. Multiple drugs have been developed order diminish stress. However, synthetic suffer from various drawbacks such cost side effects. On other hand, naturally occurring compounds are interest due their minimal valuable biological activities. Melatonin hormone pineal gland which found different plants. This compound has favorable therapeutic activities antioxidant, anti‐inflammatory, anti‐tumor, anti‐diabetic, cardioprotection. At present review, we demonstrate that Nrf2 explains some melatonin.

Language: Английский

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Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(18), P. 9964 - 9972

Published: April 20, 2020

Significance IDH1 mutation is a common genetic abnormality in human malignancies, whereas selective therapeutics for IDH1-mutated malignancies remain unavailable. Our present study reveals that cancer cells exhibit addiction to Nrf2-governed antioxidative pathways. Blockade of Nrf2 transcriptional activity achieved synergistic lethality with neomorphic mutation. We also showed triptolide serves as potent inhibitor, which inhibited and led apoptotic changes via redox catastrophe. believe our findings highlight the broad scope significance blockade therapeutic strategy provide an actionable malignancies.

Language: Английский

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Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway

Antioxidants, Journal Year: 2021, Volume and Issue: 10(6), P. 823 - 823

Published: May 21, 2021

Ischemia/reperfusion (I/R) injury is associated with substantial clinical implications, including a wide range of organs such as the brain, kidneys, lungs, heart, and many others. I/R (IRI) occurs due to tissue following reestablishment blood supply ischemic tissues, leading enhanced aseptic inflammation stimulation oxidative stress via reactive oxygen nitrogen species (ROS/RNS). Since ROS causes membrane lipids' peroxidation, triggers loss integrity, denaturation proteins, DNA damage, cell death, plays critical part in pathogenesis. Therefore, regulation could be promising therapeutic strategy for IRI. In this context, Nrf2 (NF-E2-related factor 2) transcription that regulates expression several factors involved cellular defense against inflammation, heme oxygenase-1 (HO-1). Numerous studies have shown potential role Nrf2/HO-1 pathway IRI; thus, we will review molecular aspects Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE) signaling I/R, also highlight recent insights into targeting preventing

Language: Английский

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Nrf2: The Master and Captain of Beta Cell Fate

Trends in Endocrinology and Metabolism, Journal Year: 2020, Volume and Issue: 32(1), P. 7 - 19

Published: Nov. 23, 2020

Language: Английский

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Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds?

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(15), P. 8223 - 8223

Published: July 30, 2021

Nrf2 (nuclear factor erythroid 2-related 2) and NF-κB factor–kappa B) signaling pathways play a central role in suppressing or inducing inflammation angiogenesis processes. Therefore, they are involved many steps of carcinogenesis through cooperation with multiple molecules pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention therapy. Several hundreds phytochemicals, mainly edible plant vegetable components, were shown to activate mediate antioxidant response. A similar number phytochemicals was revealed affect NF-κB. While activation inhibition protect normal cells against initiation promotion, enhanced expression lead resistance conventional chemo- radiotherapy. Most different mechanisms, Nrf2, but others, such as luteolin, can act inhibitors Despite experimental data confirming the above mechanisms currently, limited evidence exists demonstrating activity humans. Combinations resembling that natural food matrix allowing higher concentrations improve their modulating effect on ultimately prevention This review presents current knowledge selected combinations activities context.

Language: Английский

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