Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.
As a first line anti-diabetes drug, the molecular mechanisms by which metformin exerts its pharmacological activities are still under extensive investigations. The Nrf2 signaling plays a crucial role in protecting cells from oxidative damages, and has emerged as a promising target for treatment of diabetes and related complexes in recent years. In the present study, the effect of metformin on Nrf2 signaling was tested in vitro and in vivo, and the possible mechanism was explored. Metformin activated AMPK and Nrf2 signaling and induced the expression of antioxidant genes NQO1 and y-GCSm in C2C12 mouse myoblast cells in a similar concentration- and time-dependent manner. Moreover, overexpression of AMPK significantly elevated the basal and metformin-induced ARE-driven luciferase reporter activities, suggesting the involvement of AMPK in metformin-activated Nrf2 signaling. Finally, metformin activated Nrf2 signaling and induced the expression of antioxidant genes such as HO-1 and SOD, and resulted in increased GSH level in mouse liver and skeletal muscle tissues. Take together, our results clearly demonstrated that metformin activated Nrf2 signaling and enhanced the tissue antioxidant capacity, and provide a new molecular mechanism of action of metformin.
Hematological toxicity （bone marrow suppression） is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 （Nrf2） is a pivotal coordinator of cellular defensive responses against chemical insults in many tissues including bone marrow. In the present study, the effects of tert-butylhydroquinone （tBHQ） on the expression of Nrf2-regulated genes in peripheral blood cells and cyclophosphamide （CTX）-induced hematotoxicity in mice were investigated. CTX induced apoptosis of peripheral blood nucleated cells and leukopenia in mice, accompanied by mobilization of bone marrow hematopoietic cells, tBHQ treatment induced the expression of Nrf2-regulated genes such as heine oxygenase 1 （HO1） and glutamate-cysteine ligase catalytic subtmit （GCLC） in RAW264.7 mouse macrophage cells and peripheral blood cells both in vitro and in vivo. Interestingly, pretreatment with tBHQ alleviated CTX-induced mouse peripheral blood cell apoptosis and leukopenia in vivo, indicating possible involvement of Nrf2 in the protection against CTX-induced hematotoxicity. This study provides new information on the chemotherapy-induced hematotoxicity, and suggests Nrf2 could serve as a target for the development of chemoprotectants against hematotoxicity.
Chemotherapy and chemoprevention have been two of the most important means to control cancer incidence and mortality, and the cellular defensive machinery against oxidative/electrophilic stresses plays significant roles in both means. This defensive system is composed of cytoprotective enzymes that metabolize and eliminate oxidative/electrophitic species. The transcription factor nuclear factor erythroid 2-related factor 2 （Nrf2） controls the basal and inducible expression of many cytoprotective genes, and plays a pivotal role in coordinating cellular defensive responses. Under basal conditions, the activity of Nrf2 is inhibited by binding to Kelch-like ECH-associated protein 1 （Keap 1）, which is capable of sensing oxidative/electrophilic signals. Upon oxidative/electrophilic stresses, the binding of Nrf2 to Keapl is disrupted, leading to activation of Nrf2 and induction of cytoprotective enzymes. Thus, Nrf2 has emerged as an important target of chemopreventive drugs. However, activation of Nrf2 could lead to very different outcomes depending on the cellular context. The indiscriminative protective effects of Nrf2 lead to its undesired functions in carcinogenesis and chemoresistance of cancer cells. Activation of Nrf2 provides neoplastic cells with growth advantages and protects cancer cells from chemotherapeutic drugs, resulting in poor clinical outcomes. In this means, inhibitors of Nrf2 signaling can enhance the efficacy of chemotherapeutic drugs and deserve further development. A better understanding of the regulation and functions of Nrf2 would be helpful for researches in both chemoprevention and chemotherapy of cancer.
