PMID- 33920029
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220503
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 8
DP  - 2021 Apr 14
TI  - KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung 
      Cancer.
LID - 10.3390/cancers13081885 [doi]
LID - 1885
AB  - Artesunate is the most common treatment for malaria throughout the world. 
      Artesunate has anticancer activity likely through the induction of reactive 
      oxygen species, the same mechanism of action utilized in Plasmodium falciparum 
      infections. Components of the kelch-like ECH-associated protein 1 (KEAP1)/nuclear 
      factor erythroid 2-related factor 2 (NRF2) pathway, which regulates cellular 
      response to oxidative stress, are mutated in approximately 30% of non-small-cell 
      lung cancers (NSCLC); therefore, we tested the hypothesis that KEAP1 is required 
      for artesunate sensitivity in NSCLC. Dose response assays identified A549 cells, 
      which have a G333C-inactivating mutation in KEAP1, as resistant to artesunate, 
      with an IC50 of 23.6 microM, while H1299 and H1563 cells were sensitive to 
      artesunate, with a 10-fold lower IC50. Knockdown of KEAP1 through siRNA caused 
      increased resistance to artesunate in H1299 cells. Alternatively, the 
      pharmacological inhibition of NRF2, which is activated downstream of KEAP1 loss, 
      by ML385 partially restored sensitivity of A549 cells to artesunate, and the 
      combination of artesunate and ML385 was synergistic in both A549 and H1299 cells. 
      These findings demonstrate that KEAP1 is required for the anticancer activity of 
      artesunate and support the further development of NRF2 inhibitors to target 
      patients with mutations in the KEAP1/NRF2 pathway.
FAU - Hill, Kristen S
AU  - Hill KS
AUID- ORCID: 0000-0003-3757-2822
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
FAU - McDowell, Anthony
AU  - McDowell A
AD  - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 
      College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
FAU - McCorkle, J Robert
AU  - McCorkle JR
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
FAU - Schuler, Erin
AU  - Schuler E
AD  - Department of Pathology, College of Medicine, University of Kentucky, Lexington, 
      KY 40508, USA.
FAU - Ellingson, Sally R
AU  - Ellingson SR
AD  - Division of Biomedical Informatics, College of Medicine, University of Kentucky, 
      Lexington, KY 40506, USA.
FAU - Plattner, Rina
AU  - Plattner R
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Kentucky, Lexington, KY 40508, USA.
FAU - Kolesar, Jill M
AU  - Kolesar JM
AUID- ORCID: 0000-0003-1802-6439
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
AD  - Department of Pharmacy Practice and Research, College of Pharmacy, University of 
      Kentucky, Lexington, KY 40508, USA.
LA  - eng
GR  - P30 CA177558/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20210414
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC8070990
OTO - NOTNLM
OT  - KEAP1
OT  - NRF2
OT  - NSCLC
OT  - artesunate
COIS- The authors declare no conflict of interest.
EDAT- 2021/05/01 06:00
MHDA- 2021/05/01 06:01
PMCR- 2021/04/14
CRDT- 2021/04/30 01:14
PHST- 2021/02/22 00:00 [received]
PHST- 2021/04/08 00:00 [revised]
PHST- 2021/04/09 00:00 [accepted]
PHST- 2021/04/30 01:14 [entrez]
PHST- 2021/05/01 06:00 [pubmed]
PHST- 2021/05/01 06:01 [medline]
PHST- 2021/04/14 00:00 [pmc-release]
AID - cancers13081885 [pii]
AID - cancers-13-01885 [pii]
AID - 10.3390/cancers13081885 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 Apr 14;13(8):1885. doi: 10.3390/cancers13081885.