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Review
. 2021 Feb 26;10(3):349.
doi: 10.3390/antiox10030349.

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Sepideh Mirzaei  1 , Ali Zarrabi  2 , Farid Hashemi  3 , Amirhossein Zabolian  4 , Hossein Saleki  4 , Negar Azami  4 , Soodeh Hamzehlou  4 , Mahdi Vasheghani Farahani  4 , Kiavash Hushmandi  5 , Milad Ashrafizadeh  2   6 , Haroon Khan  7 , Alan Prem Kumar  8   9
Affiliations
Review

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Sepideh Mirzaei et al. Antioxidants (Basel). .

Abstract

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

Keywords: chemoresistance; doxorubicin; nuclear factor erythroid 2-related factor 2 (Nrf2), cancer therapy; oxidative stress; redox signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A schematic presentation of Nrf2 signaling pathway. Oxidative stress induces nuclear translocation of Nrf2 to promote antioxidant activity via up-regulating HO-1, NQO1, and GCLM.
Figure 2
Figure 2
Targeting Nrf2 signaling pathway in chemoprotection. Regulation of Nrf2 signaling by upstream mediators and protective compounds in decreasing adverse effects of doxorubicin. Apoptosis, mitochondrial dysfunction, necrosis and cell death are prevented upon Nrf2 activation.
Figure 3
Figure 3
Nrf2 signaling in mediating DOX resistance of cancer cells. Suppressing Nrf2 signaling as a pro-survival pathway is associated with induction of apoptosis and necrosis in cancer cells, and their sensitivity to chemotherapy.
See this image and copyright information in PMC

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