The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones

Abstract

Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2⁻ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2⁻ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.

Keywords: Keap1; NF-κB; Nrf2; anti-inflammatory activity; antioxidant activity; chalcones; multi-target activity.

Figure 1

Chalcone structure (a) and its Michael addition with cysteine (b).

Figure 2

Mechanisms of Nrf2–ARE pathway activation by Michael acceptors. (a) Under baseline conditions, Nrf2 forms a complex with Keap1 in the cytosol, which facilitates the ubiquitination and degradation of Nrf2 by the proteasome. (b) The dissociation of the Nrf2–Keap1 complex is an essential prerequisite for Nrf2/ARE activation by Michael acceptors that happens through two mechanisms: (i) by modification of the cysteines in Keap1, which leads to conformational changes in this protein and the subsequent release of Nrf2; (ii) by activation of kinases that phosphorylate Nrf2 and thereby free it from Keap1-mediated complex. After nuclear translocation, Nrf2 binds to ARE in the promoter regions of various detoxification, antioxidant and anti-inflammatory genes. Nrf2, Nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; ARE, antioxidant response element; Ub, ubiquitin; P, phosphate.

Figure 3

Multi-target interaction of chalcones on cross-talk between Nrf2 and NF-κB response pathways involved in inflammation. Nrf2, Nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; ARE, antioxidant response element; P, phosphate; ERK1/2, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; p38-MAPK, p38-mitogen activated protein kinase; NF-κB, nuclear factor-κB; IκBα, nuclear κ-B inhibitor; IKK, IκB kinase.