PMID- 27344172
OWN - NLM
STAT- MEDLINE
DCOM- 20180302
LR  - 20181202
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 30
DP  - 2016 Jul 26
TI  - NRF2 and glutathione are key resistance mediators to temozolomide in glioma and 
      melanoma cells.
PG  - 48081-48092
LID - 10.18632/oncotarget.10129 [doi]
AB  - 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.
FAU - Rocha, Clarissa Ribeiro Reily
AU  - Rocha CR
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Kajitani, Gustavo Satoru
AU  - Kajitani GS
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Quinet, Annabel
AU  - Quinet A
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Fortunato, Rodrigo Soares
AU  - Fortunato RS
AD  - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de 
      Janeiro, Rio de Janeiro, Brazil.
FAU - Menck, Carlos Frederico Martins
AU  - Menck CF
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 5072-26-4 (Buthionine Sulfoximine)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - GAN16C9B8O (Glutathione)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/*pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology
MH  - Brain Neoplasms/*drug therapy/metabolism/pathology
MH  - Buthionine Sulfoximine/administration & dosage
MH  - Cell Line, Tumor
MH  - Dacarbazine/administration & dosage/*analogs & derivatives/pharmacology
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Glioma/*drug therapy/metabolism/pathology
MH  - Glutathione/*metabolism
MH  - Humans
MH  - Melanoma/*drug therapy/metabolism/pathology
MH  - Melanoma, Experimental/drug therapy/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Nude
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Temozolomide
MH  - Xenograft Model Antitumor Assays
PMC - PMC5217002
OTO - NOTNLM
OT  - NRF2
OT  - glioma
OT  - melanoma
OT  - resistance
OT  - temozolomide
COIS- Conflicts of Interest: None declared.
EDAT- 2016/06/28 06:00
MHDA- 2018/03/03 06:00
PMCR- 2016/07/26
CRDT- 2016/06/27 06:00
PHST- 2016/03/31 00:00 [received]
PHST- 2016/06/06 00:00 [accepted]
PHST- 2016/06/28 06:00 [pubmed]
PHST- 2018/03/03 06:00 [medline]
PHST- 2016/06/27 06:00 [entrez]
PHST- 2016/07/26 00:00 [pmc-release]
AID - 10129 [pii]
AID - 10.18632/oncotarget.10129 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Jul 26;7(30):48081-48092. doi: 10.18632/oncotarget.10129.