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.
Highlights
Doxorubicin (DOX) is an anthracycline isolated from Streptomyces with proficiency in treatment of various cancers such as thoracic cancers, reproductive cancers, gastrointestinal and brain tumors [1]
We focus on a molecular pathway which involves nuclear factor erythroid 2-related factor 2 (Nrf2) as a regulator of oxidative stress in cells
Sequestration of Nuclear factor erythroid 2-related factor 2 (Nrf2) occurs in normal conditions by Kelchlike ECH-associated protein 1 (Keap1), when reactive oxygen species (ROS) and oxidative levels are at standard limit [45]
Summary
Doxorubicin (DOX) is an anthracycline isolated from Streptomyces with proficiency in treatment of various cancers such as thoracic cancers, reproductive cancers, gastrointestinal and brain tumors [1]. In non-small cell lung cancer, vasohibin (VASH2) functions as a tumor-promoting factor in enhancing proliferation that subsequently, stimulates DOX resistance [12] Identification of such factors is of importance in suppressing DOX resistance by developing potential therapeutics for their targeting [13]. In addition to recognition of tumor-promoting molecular pathways and using combination chemotherapy, another strategy that utilizes nanostructures for DOX delivery has been developed This strategy is ideal for in vitro and in vivo experiments and nanoparticles can provide a platform for co-delivery of DOX with other anti-tumor agents, leading to targeted delivery at tumor site and reversing chemoresistance [22]. The DOX resistance is an increasing challenge, and more experiments are required to find novel strategies in reversing chemoresistance Another obstacle in using DOX in cancer chemotherapy is its dose-dependent toxicity. Activation of Nrf signaling protects cells against oxidative damage [31], it can induce chemoresistance via suppressing oxidative-mediated cell death in cancer cells [32]
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