4.7 Article

Inhibition of the NRF2/KEAP1 Axis: A Promising Therapeutic Strategy to Alter Redox Balance of Cancer Cells

Journal

ANTIOXIDANTS & REDOX SIGNALING
Volume 34, Issue 18, Pages 1428-1483

Publisher

MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2020.8146

Keywords

NRF2-KEAP1; NRF2 inhibitors; reactive oxygen species; oxidative stress; cancer; chemotherapy; redox therapy

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The NRF2/KEAP1 pathway is crucial for maintaining cellular homeostasis in response to stress conditions. Deregulated NRF2 activation is linked to malignant tumors, while targeting NRF2 may offer therapeutic potential in cancer treatment. Further research is needed to identify specific NRF2 inhibitors for clinical benefit.
Significance: The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) pathway is a crucial and highly conserved defensive system that is required to maintain or restore the intracellular homeostasis in response to oxidative, electrophilic, and other types of stress conditions. The tight control of NRF2 function is maintained by a complex network of biological interactions between positive and negative regulators that ultimately ensure context-specific activation, culminating in the NRF2-driven transcription of cytoprotective genes. Recent Advances: Recent studies indicate that deregulated NRF2 activation is a frequent event in malignant tumors, wherein it is associated with metabolic reprogramming, increased antioxidant capacity, chemoresistance, and poor clinical outcome. On the other hand, the growing interest in the modulation of the cancer cells' redox balance identified NRF2 as an ideal therapeutic target. Critical Issues: For this reason, many efforts have been made to identify potent and selective NRF2 inhibitors that might be used as single agents or adjuvants of anticancer drugs with redox disrupting properties. Despite the lack of specific NRF2 inhibitors still represents a major clinical hurdle, the researchers have exploited alternative strategies to disrupt NRF2 signaling at different levels of its biological activation. Future Directions: Given its dualistic role in tumor initiation and progression, the identification of the appropriate biological context of NRF2 activation and the specific clinicopathological features of patients cohorts wherein its inactivation is expected to have clinical benefits, will represent a major goal in the field of cancer research. In this review, we will briefly describe the structure and function of the NRF2/ KEAP1 system and some of the most promising NRF2 inhibitors, with a particular emphasis on natural compounds and drug repurposing.

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