Nrf2 in cancers: A double‐edged sword

Abstract

The Nrf2/Keap1 pathway is an important signaling cascade responsible for the resistance of oxidative damage induced by exogenous chemicals. It maintains the redox homeostasis, exerts anti‐inflammation and anticancer activity by regulating its multiple downstream cytoprotective genes, thereby plays a vital role in cell survival. Interestingly, in recent years, accumulating evidence suggests that Nrf2 has a contradictory role in cancers. Aberrant activation of Nrf2 is associated with poor prognosis. The constitutive activation of Nrf2 in various cancers induces pro‐survival genes and promotes cancer cell proliferation by metabolic reprogramming, repression of cancer cell apoptosis, and enhancement of self‐renewal capacity of cancer stem cells. More importantly, Nrf2 is proved to contribute to the chemoresistance and radioresistance of cancer cells as well as inflammation‐induced carcinogenesis. A number of Nrf2 inhibitors discovered for cancer treatment were reviewed in this report. These provide a new strategy that targeting Nrf2 could be a promising therapeutic approach against cancer. This review aims to summarize the dual effects of Nrf2 in cancer, revealing its function both in cancer prevention and inhibition, to further discover novel anticancer treatment.

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Activation of the NRF2 system is complex and can follow canonical and non-canonical pathways. A difficulty in identifying activators and inhibitors of NRF2 or KEAP1 as modulators of inflammation and potential protectors against oxidative stress and carcinogenesis, is the dual nature of the NRF2-KEAP1 protein-protein interaction [26,[59][60][61][62]. Generally, activation of NRF2 has been viewed as therapeutic, but recent evidence has suggested that this event can be pro-oncogenic as well, depending on the context of NRF2 activation [62].…”

“…Whereas new findings indicate that NRF2 plays a dual role in cancer ( [26,105,106], the potential use of NRF2 activators in cancer prevention and therapy needs to be further elucidated. It is widely accepted that effective chemoprevention should encompass induction of cytoprotective and detoxifying enzymes.…”

“…Disruption of NRF2 signaling is a promising therapeutic approach against NRF2-addicted cancers and some effective NRF2 inhibitors such as brusatol and halofuginone have been employed, while many others are under investigation. Nevertheless, administration of systemic NRF2 inhibitors may cause off-target effects on patients and this represents a key aspect for the identification of novel compounds that should ideally possess high specificity, bioactivity and limited side-toxicity [26]. To prevent these side effects, mechanistic insights should be revealed and new pharmacological targets besides NRF2 should be studied.…”

“…Most of these molecules lack specificity and have off-target toxic effects since they easily react with cysteine residues of different molecules. Metabolic instability, low bioavailability, and poor membrane permeability are some of the basic drawbacks in the administration of many NRF2 inhibitors [26]. To date, dimethyl fumarate is the only NRF2 activator approved by the Food and Drug Administration (FDA) but its function in cancer prevention has not been examined yet.…”

Dietary Cocoa Prevents Aortic Remodeling and Vascular Oxidative Stress in Diabetic Rats

“…Accordingly, the increase of Nrf2 activity by several activators has been considered as a promising approach for preventing the development of vascular complications in diabetes. However, constitutive activation of Nrf2 has been also found in a variety of cancers; therefore, additional studies about the role of Nrf2 activation in specific tissues are necessary to better understand the multiple roles of Nrf2 in diabetes.…”