Nrf2: a potential therapeutic target for naturally occurring anticancer drugs?

ABSTRACT

Introduction: Nuclear factor (erythroid-derived-2)-like 2 is one of the most efficient cytoprotective rheostats against exogenous or endogenous oxidative insults. At present, the modulation of the Nrf2 pathway represents an interesting and highly explored strategy in the oncological area.

Area covered: In this review, we present and discuss the different modulation of the Nrf2 pathway by some natural compounds with a well demonstrated anticancer activity, and critically analyze the challenges associated with the development of an Nrf2-based anticancer strategy.

Expert opinion: Many natural compounds with a well-defined anticancer activity are able to modulate this pathway. Both Nrf2 inducers and inhibitors can be useful as anticancer strategy. However, since Nrf2 modulates many networks potentially involved in the detoxification process of anticancer drugs, its activation in cancer cells could lead to chemoresistance. The switch between a beneficial or detrimental role of Nrf2 in cancer cells essentially depends on the tight control of its activity, the specific conditions of tumor microenvironment, and cell type. In line with the paucity of clear data related to the mechanisms underpinning the role of Nrf2 in cancer development and chemoresistance, discovery and development of Nrf2-based strategies is one of the most critical and challenging assignments for fighting cancers.

KEYWORDS:

• Nrf2
• natural anticancer compounds
• sulforaphane
• resveratrol
• brusatol
• chemoresistance
• chemosensitization
• cancer chemoprevention and therapy

Article highlights

• The transcription factor Nrf2 drives a cytoprotective pathway involved in the regulation of oxidative environment. Since Nrf2 modulates many networks potentially involved in the detoxification process of anticancer drugs, its activation in cancer cells could lead to chemoresistance.

• SFN targets Nrf2 at different levels. The induction of Nrf2 by SFN doesn’t lead to chemoresistance probably due to the ability of SFN to interact with other pathways involved in tumor resistance.

• RESV is a hormetic regulator of Nrf2: at low concentrations (specific for each cell type), allegedly those at which RESV induces cancer chemoprevention, it promotes Nrf2 activation, while at higher concentrations it is a negative Nrf2 modulator.

• BRU is an inhibitor of protein synthesis and a negative modulator of Nrf2. It leads to an increase in the oxidative status of cells that become more sensitive to anticancer drugs.

• Other negative modulators, such as ascorbic acid, trigonellin, luteolin, and wogonin have chemosensitizing properties but they have been poorly studied.

• CUR is an interesting Nrf2 inducer, but its low bioavailability restrains its potential clinical use.

• Both Nrf2 inducers and inhibitors can be useful in cancer therapy. The switch between a beneficial or detrimental role of Nrf2 in cancer cells essentially depends on the tight control of its activity and the cellular type and environment

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded