PMID- 31776385
OWN - NLM
STAT- MEDLINE
DCOM- 20201102
LR  - 20210110
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Nov 27
TI  - The balance between NRF2/GSH antioxidant mediated pathway and DNA repair 
      modulates cisplatin resistance in lung cancer cells.
PG  - 17639
LID - 10.1038/s41598-019-54065-6 [doi]
LID - 17639
AB  - Lung cancer patients face a dismal prognosis mainly due to the low efficacy of 
      current available treatments. Cisplatin is the first-line chemotherapy treatment 
      for those patients, however, resistance to this drug is a common and yet not 
      fully understood phenomenon. Aiming to shed new light into this puzzle, we used 
      established normal and malignant lung cell lines displaying different sensitivity 
      towards cisplatin treatment. We observed a negative correlation between cell 
      viability and DNA damage induction upon cisplatin treatment. Interestingly, drug 
      sensitivity in those cell lines was not due to either difference on DNA repair 
      capacity, or in the amount of membrane ion channel commonly used for cisplatin 
      uptake. Also, we noted that glutathione intracellular levels, and expression and 
      activity of the transcription factor nuclear factor erythroid 2-related factor 2 
      (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene 
      expression in non-small cell lung cancer patients of the TCGA data bank revealed 
      that there is a significant lower overall survival rate in the subset of patients 
      bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, 
      increased expression of NRF2 target genes. Thus, the results indicate that NRF2 
      and glutathione levels figure as important cisplatin resistance biomarkers in 
      lung cancer.
FAU - Silva, Matheus Molina
AU  - Silva MM
AUID- ORCID: 0000-0002-8917-8600
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Rocha, Clarissa Ribeiro Reily
AU  - Rocha CRR
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
AD  - Department of Experimental and Clinical Oncology, Federal University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Kinker, Gabriela Sarti
AU  - Kinker GS
AD  - Department of Physiology, Institute of Biosciences, University of Sao Paulo, Sao 
      Paulo, Brazil.
FAU - Pelegrini, Alessandra Luiza
AU  - Pelegrini AL
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Menck, Carlos Frederico Martins
AU  - Menck CFM
AUID- ORCID: 0000-0003-1941-0694
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil. cfmmenck@usp.br.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191127
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antioxidants)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - GAN16C9B8O (Glutathione)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - A549 Cells/drug effects/metabolism
MH  - Antineoplastic Agents/*therapeutic use
MH  - Antioxidants/metabolism
MH  - Biomarkers, Tumor/metabolism
MH  - Blotting, Western
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Cisplatin/*therapeutic use
MH  - *DNA Repair/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance, Neoplasm
MH  - Flow Cytometry
MH  - Glutathione/*metabolism
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/metabolism
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - *Signal Transduction/drug effects
PMC - PMC6881285
COIS- The authors declare no competing interests.
EDAT- 2019/11/30 06:00
MHDA- 2020/11/03 06:00
PMCR- 2019/11/27
CRDT- 2019/11/29 06:00
PHST- 2019/03/11 00:00 [received]
PHST- 2019/09/23 00:00 [accepted]
PHST- 2019/11/29 06:00 [entrez]
PHST- 2019/11/30 06:00 [pubmed]
PHST- 2020/11/03 06:00 [medline]
PHST- 2019/11/27 00:00 [pmc-release]
AID - 10.1038/s41598-019-54065-6 [pii]
AID - 54065 [pii]
AID - 10.1038/s41598-019-54065-6 [doi]
PST - epublish
SO  - Sci Rep. 2019 Nov 27;9(1):17639. doi: 10.1038/s41598-019-54065-6.