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

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 conc...

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Bibliographic Details
Published in:Antioxidants 2021-02, Vol.10 (3), p.349
Main Authors: Mirzaei, Sepideh, Zarrabi, Ali, Hashemi, Farid, Zabolian, Amirhossein, Saleki, Hossein, Azami, Negar, Hamzehlou, Soodeh, Farahani, Mahdi Vasheghani, Hushmandi, Kiavash, Ashrafizadeh, Milad, Khan, Haroon, Kumar, Alan Prem
Format: Article
Language:English
Subjects:
Antioxidants
Apoptosis
Brain cancer
Cancer
Cancer therapies
cancer therapy
Cell death
Chemoprotection
Chemoresistance
Chemotherapy
Doxorubicin
Drug dosages
Drug resistance
Experiments
Free radicals
Hypoxia
Inflammation
Kinases
Medical prognosis
nuclear factor erythroid 2-related factor 2 (Nrf2)
Oxidative stress
Proteins
Reactive oxygen species
redox signaling
Review
Side effects
Signal transduction
Toxicity
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Summary: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.
ISSN:2076-3921
2076-3921
DOI:10.3390/antiox10030349