Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs

Abstract

Oxidative stress (OS) is associated with many diseases ranging from cancer to neurodegenerative disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is one of the most effective cytoprotective controller against OS. Modulation of Nrf2 pathway constitutes a remarkable strategy in the antineoplastic treatments. A big number of Nrf2-antioxidant response element activators have been screened for use as chemo-preventive drugs in OS associated diseases like cancer even though activation of Nrf2 happens in a variety of cancers. Research proved that hyperactivation of the Nrf2 pathway produces a situation that helps the survival of normal as well as malignant cells, protecting them against OS, anticancer drugs, and radiotherapy. In this review, the modulation of the Nrf2 pathway, anticancer activity and challenges associated with the development of an Nrf2-based anti-cancer treatment approaches are discussed.

Keywords: Nrf2 inhibitors; antineoplastic drugs; cancer; cancer chemoprevention and therapy; chemoresistance.

Figure 1

Nrf2 status in normal and cancer cells. (A) In a normal cell, under normal conditions Keap1 inhibits transcriptional activity of Nrf2 via ubiquitination and proteasomal degradation, under stress conditions Keap1 and Nrf2 interaction does not occur, causing Nrf2 stabilization and accumulation in nucleus, which in turn induces cytoprotective gene expression. (B) In a cancer cell, somatic mutations in NRF2 (gain of function mutations) and KEAP1 (loss of function mutations) result in constitutive activation of Nrf2 inducing expression of genes related to tumorigenity. Nrf2, nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; Maf, small musculoaponeurotic fibrosarcoma protein; Pol II; Polimerase II; ARE: Antioxidant response element