Controversy about pharmacological modulation of Nrf2 for cancer therapy

Abstract

Conventional anticancer therapies such as radiotherapy and chemotherapies are associated with oxidative stress generating reactive oxygen species (ROS) and reactive aldehydes like 4-hydroxynonenal in cancer cells that govern them to die. The main mechanism activated due to exposure of the cell to these reactive species is the Nrf2-Keap1 pathway. Although Nrf2 was firstly perceived as a tumor suppressor that inhibits tumor initiation and cancer metastasis, more recent data reveal its role also as a pro-oncogenic factor. Discovery of the upregulation of Nrf2 in different types of cancer supports such undesirable pathophysiological roles of Nrf2. The upregulation of Nrf2 leads to activation of cytoprotective genes thus helping malignant cells to withstand high levels of ROS and to avoid apoptosis, eventually becoming resistant to conventional anticancer therapy. Therefore, new treatment strategies are needed for eradication of cancer and in this review, we will explore two opposing approaches for modulation of Nrf2 in cancer treatments.

Keywords: 4-hydroxynonenal; Cancer; Cancer therapy; Growth regulation; Nrf2; Oxidative stress.

Graphical abstract

Fig. 1

Schematic overview of the Nrf2 pathway. In homeostatic conditions, transcription factor Nrf2 is bound to its repressor Keap1 and thus subjected to ubiquitin-dependent degradation in proteasomes. On the other hand, in stress conditions, Nrf2 released from Keap1 is translocated into nucleus where it forms heterodimers with small Maf proteins and activates cytoprotective genes through antioxidant response element (ARE).

Fig. 2

Activation of Nrf2 has dual role in carcinogenesis. In carcinogenesis Nrf2 was recognized to have a dual role: protective in early stages and detrimental in later stages. Indeed, in early stages, sufficient Nrf2 levels maintain homeostasis by eliminating carcinogens, such as ROS and other DNA-damaging agents, and thus inhibit tumor initiation and cancer metastasis. Whereas, in cancer, Nrf2 is usually upregulated leading to activation of cytoprotective genes and thus helping malignant cells to endure high levels of ROS and avoid apoptosis.

Fig. 3

Simplified schematic overview of interaction of Nrf2 activators and inhibitors in anticancer therapy. Majority of conventional therapy against cancer relies on generation of ROS resulting in cancer cell death. Yet, not all cancer cells are affected and they tend to become resistant. Although, diverse mechanisms contribute to perceived resistance, this therapy-induced increase of redox imbalance requires involvement of the Nrf2-Keap1 pathway which is the main regulator of cytoprotective responses. Observation that a single nucleotide polymorphism in the human Nrf2, leading to reduced Nrf2 gene expression, increases risk of lung cancer supported Nrf2 protective role. In addition, due to the fact that Nrf2 inhibits tumor initiation and cancer metastasis by eliminating carcinogens, ROS and other DNA-damaging agents, a variety of its natural and synthetic activators have been implicated in prevention of cancer development (e.g. sulforaphane, oleanane triterpenoid RTA 405, etc.). Some of them have also shown their beneficial role during cancer therapy by affecting other mechanism. Examples are: RTA405 which was found to decrease NF-κB activity and thus suppress cancer cell survival and promote apoptosis and sulforaphane (SFN) which selective cytotoxicity of cancer cells involves generation of HNE (A). Yet, caution in using Nrf2 activators was suggested since they have been implicated in enhanced cancer cell resistance. Due to the fact that in many cancers, especially in later stages of the disease, Nrf2 and Keap1 are mutated leading to Nrf2 increased activity, inhibitors of Nrf2 were suggested to be a promising tool that will sensitize cancer cells and increase efficacy of conventional therapy (B). Though, both, Nrf2 activators and inhibitors have shown to be beneficial, e.g. activators mainly in prevention of cancer incidence and inhibitors during progression of the disease, there is a lot of uncertainties that is pushing us to unveil all the modalities by which Nrf2 can be used as a therapeutic target.