NRF2 and glutathione are key resistance mediators to temozolomide in glioma and melanoma cells

// Clarissa Ribeiro Reily Rocha 1 , Gustavo Satoru Kajitani 1 , Annabel Quinet 1 , Rodrigo Soares Fortunato 2 , Carlos Frederico Martins Menck 1 1 Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil 2 Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Correspondence to: Carlos Frederico Martins Menck, email: cfmmenck@usp.br Keywords: temozolomide, resistance, glioma, melanoma, NRF2 Received: March 31, 2016     Accepted: June 06, 2016     Published: June 17, 2016 ABSTRACT Cancer is a leading cause of death worldwide, and while great advances have been made particularly in chemotherapy, many types of cancer still present a dismal prognosis. In the case of glioma, temozolomide (TMZ) is the main option for treatment, but it has limited success due to drug resistance. While this resistance is usually associated to DNA repair mechanisms, in this work we demonstrate that oxidative stress plays an important role. We showed that upon TMZ treatment there is an induction of the nuclear factor erythroid 2-related factor 2 (NRF2), which is the main antioxidant transcription factor regulator in human cells. This is accompanied by an enhancement of glutathione (GSH) concentration in the tumor cells. The effectiveness of this pathway was proven by silencing NFR2, which greatly enhanced cell death upon TMZ treatment both in vitro and in vivo . Also, higher DNA damage and induced cell death was observed by combining BSO - a GSH inhibitor - with TMZ. Similar effects were also observed using in vitro and in vivo models of melanoma, thus possibly indicating that GSH has a decisive role in TMZ resistance in a wider range of tumors. Thus, a combined regimen of BSO and TMZ configures an interesting therapeutic alternative for fighting both glioma and melanoma.