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The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives.

ABSTRACT: The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review.

SUBMITTER: Panieri E

PROVIDER: S-EPMC7277620 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives.

Panieri Emiliano E Telkoparan-Akillilar Pelin P Suzen Sibel S Saso Luciano L

Biomolecules 20200520 5

The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid thera ...[more]

PMID: 32443774

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Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals.

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| S-EPMC7699726 | biostudies-literature

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Impaired antioxidant KEAP1-NRF2 system in amyotrophic lateral sclerosis: NRF2 activation as a potential therapeutic strategy.

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Project description: Not available

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Project description:The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. Considering the increasing interest of discovering novel NRF2 activators due to its clinical application, initial efforts were devoted to the development of electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through covalent modifications on cysteine residues. However, off-target effects of these drugs prompted the development of an innovative strategy, the search of KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative activators are proposed to target NRF2 in a more selective way, leading to potentially improved drugs with the application for a variety of diseases that are currently under investigation. In this review, we summarize known KEAP1-NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.

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