Nrf2 sensitizes cancer cells to chemotherapeutic agents

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Nrf2 is a critical regulator of antioxidants and detoxification enzymes, which confer cells a cytoprotective response to various adverse stresses. In this study, we investigated if Nrf2 is involved in the protection of cancer cells against the adverse environment exerted from chemotherapeutic drugs and makes contribution to drug resistance frequently occurring in cancer chemotherapy. Our data strongly showed that stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin, and etoposide. In contrast, down-regulation of the Nrf2-dependent response by over-expression of Keap1 or transient-transfection of Nrf2-siRNA rendered cancer cells more susceptible to these drugs. In addition, up-regulation of Nrf2 by the small chemical tBHQ, a Nrf2 inducer, also enhanced the resistance of cancer cells. Our results demonstrated the feasibility of using Nrf2 inhibitors as adjuvants to chemotherapeutic agents to maximize killing of cancer cells. Furthermore, the Nrf2-dependent response to chemotherapeutic agents was not limited to a particular cell type or a specific class of anti-cancer drugs. Therefore, inhibiting Nrf2 during chemotherapy can be a general approach for treatment of tumors of different tissue origin