Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review

Abstract

A major cell defense mechanism against oxidative and xenobiotic stress is mediated by the Nrf2/Keap1 signaling pathway. The Nrf2/Keap1 pathway regulates gene expression of many cytoprotective and detoxifying enzymes, thus playing a pivotal role in maintaining redox cellular homeostasis. Many diseases including cancer have been closely related to impaired Nrf2 activity. Targeting Nrf2 and modulating its activity represents a novel modern strategy for cancer chemoprevention and therapy. In this review, different design strategies used for the development of Nrf2 modulators are described in detail. Moreover, the main focus is on important and recently developed Nrf2 activators and inhibitors, their in vitro and in vivo studies, and their potential use as chemopreventive agents and/or cancer therapeutics.

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

“…Such a process allows Keap1 to recognize ARE initiation transcription. [7] Intracellular endogenous antioxidant gene, such as quinone oxidoreductase-1 (NQO1), [8] superoxide dismutase (SOD), heme oxygenase-1 (HO-1), [8] glutathione s-transferases (GST), and γ-glutamylcysteine synthetase (γ-GCS) also called glutamate cysteine ligase (GCL), catalase(CAT), etc., are increased to maintain homeostasis. [9] The protein encoded by the Nrf2-target gene has a wide range of cytoprotective effects including antioxidation, detoxification, and anti-inflammatory.…”

Epigenetic treatment of dermatologic disorders

“…Not surprisingly, there is great interest in pharmacological modulators of Nrf2 that could be developed into therapeutics for the treatment and prevention of disease (Buendia et al, ; Cuadrado et al, ; Dodson et al, ; Du et al, ; Gacesa et al, ; Kumar, Kim, More, Kim, & Choi, ; Lu, Ji, Jiang, & You, ; Rabbani, Ellison, et al, ; Sivandzade et al, ; Sklirou, Papanagnou, Fokialakis, & Trougakos, ; Sova & Saso, ; Vega, Dodson, Chapman, & Zhang, ; Yamamoto et al, ; Zhang et al, ), including skin disorders (Dodson et al, ; Ferrándiz, Nacher‐Juan, & Alcaraz, ; Gacesa et al, ; Kumar et al, ; Lu et al, ; Penta, Somashekar, & Meeran, ; Rabbani, Ellison, et al, ; Son et al, ; Yamamoto et al, ). Examples of natural products known to induce epigenetic Nrf2‐activating effects are shown in Figure (Bambouskova et al, ; Dodson et al, ; Fazzari et al, ; Fratantonio et al, ; Garaude, ; Gill, Raman, Yost, Garrett, & Vedam‐Mai, ; Gu et al, ; Iranshahy, Iranshahi, Abtahi, & Karimi, ; Irwin, Moos, Faller, Steliou, & Pinkert, ; Kumar et al, ; Li et al, ; Mathers et al, ; Matzinger, Fischhuber, & Heiss, ; Moos, Maneta, et al, ; Moos et al, ; Rigacci & Stefani, ; Rusu, Gheldiu, Mocan, Vlase, & Popa, ; Sivandzade et al, ; Steliou, Boosalis, Perrine, Sangerman, & Faller, ; Steliou, Faller, Pinkert, Irwin, & Moos, ; Tsujita et al, ).…”

“…In an attempt to overcome clinical and pharmacological shortfalls, such as efficacy and/or safety issues associated with stochastic off‐target adverse effects that were exposed in clinical trials (Dodson et al, ; Patra, Mukhopadhyay, Sarkar, Mukherjee, & Chawla‐Sarkar, ; Sova & Saso, ), a wide array of synthetic and semisynthetic Nrf2‐modulators were prepared (Deck, Whalen, Hunsaker, Royer, & Jagt, ; Sivandzade et al, ; Sklirou et al, ; Sova & Saso, ). Three notable examples of synthetic Nrf2‐activating compounds that advanced to clinical trials are shown in Figure (Cuadrado et al, ; Gacesa et al, ; Naidu et al, ; Patra et al, ; Rabbani, Ellison, et al, ; Sklirou et al, ; Sova & Saso, ).…”

“…In an attempt to overcome clinical and pharmacological shortfalls, such as efficacy and/or safety issues associated with stochastic off‐target adverse effects that were exposed in clinical trials (Dodson et al, ; Patra, Mukhopadhyay, Sarkar, Mukherjee, & Chawla‐Sarkar, ; Sova & Saso, ), a wide array of synthetic and semisynthetic Nrf2‐modulators were prepared (Deck, Whalen, Hunsaker, Royer, & Jagt, ; Sivandzade et al, ; Sklirou et al, ; Sova & Saso, ). Three notable examples of synthetic Nrf2‐activating compounds that advanced to clinical trials are shown in Figure (Cuadrado et al, ; Gacesa et al, ; Naidu et al, ; Patra et al, ; Rabbani, Ellison, et al, ; Sklirou et al, ; Sova & Saso, ). Omaveloxolone (RTA 408) (Cuadrado et al, ; Dinkova‐Kostova et al, ; Dodson et al, ; Rabbani, Ellison, et al, ) shows potential in enhancing regenerative capacity of diabetic wounds (Rabbani, Ellison, et al, ) and in the treatment of patients with mitochondrial myopathies and Friedrich's ataxia (Dodson et al, ), but bardoxolone methyl (RTA 402, CDDO‐Me) (Zhou, Wang, Zhe, Yang, & He, ) and oltipraz (D3T) (Dodson et al, ; Weerachayaphorn et al, ) cause serious side effects that make their approval unlikely (Patra et al, ; Weerachayaphorn et al, ; Zhou et al, ).…”

“…This heightened expression helps to eliminate the buildup of tumorigenic cells in the epidermis in response to DNA damage‐inducing agents (Siegenthaler et al, ). The opposing, complementary functions of Nrf2 and Nrf3 further underscore a critical dilemma faced in arbitrarily overactivating Nrf2 (Dodson et al, ; Ikehata & Yamamoto, ; Menegon et al, ; Rabbani, Xue, et al, ; Silva‐Palacios et al, ; Sova & Saso, ).…”