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

• Published in: Oncotarget Vol. 7; no. 30; pp. 48081 - 48092
• Main Authors: Rocha, Clarissa Ribeiro Reily, Kajitani, Gustavo Satoru, Quinet, Annabel, Fortunato, Rodrigo Soares, Menck, Carlos Frederico Martins
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 26.07.2016
• Subjects: Animals; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Buthionine Sulfoximine - administration & dosage; Cell Line, Tumor; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Drug Resistance, Neoplasm; Female; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Glutathione - metabolism; Humans; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Mice; Mice, Inbred C57BL; Mice, Nude; NF-E2-Related Factor 2 - metabolism; Research Paper; Xenograft Model Antitumor Assays; temozolomide; glioma; melanoma; NRF2; resistance
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10129

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.