PMID- 34954641 OWN - NLM STAT- MEDLINE DCOM- 20220321 LR - 20220321 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 146 DP - 2022 Feb TI - Plumbagin reduction by thioredoxin reductase 1 possesses synergy effects with GLUT1 inhibitor on KEAP1-mutant NSCLC cells. PG - 112546 LID - S0753-3322(21)01333-0 [pii] LID - 10.1016/j.biopha.2021.112546 [doi] AB - Thioredoxin reductase 1 (TrxR1 or TXNRD1) is a major enzyme in cellular redox regulation and is considered as a drug target for cancer therapy. Previous studies have reported that plumbagin caused reactive oxygen species (ROS)-dependent apoptosis via inhibiting TrxR1 activity or being reduced by TrxR1, leading to selectively cancer cell death. However, the mechanism of TrxR1-mediated redox cycling of plumbagin is obscure and the evidence for plumbagin targeting TrxR1 is still lacking. Herein, we demonstrated that TrxR1 catalyzed plumbagin reduction in both selenocysteine (Sec)-dependent and independent manners, and its activity relied on the intact N-terminal motif of TrxR1, but a high-efficiency reduction was supported by the C-terminal thiols. During the redox cycling of plumbagin, excessive ROS production was observed coupled with oxygen. Using LC-MS and TrxR1 mutants, we found that the Sec residue of TrxR1 was modified by plumbagin, which converted the enzyme from antioxidant to pro-oxidant. Furthermore, we evaluated the therapeutic potential of plumbagin in non-small cell lung cancer (NSCLC), and found that Kelch-like ECH-associated protein 1 (KEAP1)-mutant NSCLC cells, which possess constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activity, were insensitive to plumbagin; however, inhibition of glucose transporter 1 (GLUT1) by small-molecule BAY-876 or inhibiting glucose-6-phosphate dehydrogenase (G6PD) by 6-aminonicotinamide (6-AN) overcame the plumbagin-resistance of KEAP1-mutant NSCLC cells. Taken together, this study elucidated the pharmacological mechanism of plumbagin by targeting TrxR1 and revealed the synergy effect of plumbagin and BAY-876, which may be helpful for applying naphthoquinone compounds to chemotherapy, particularly for treating KEAP1-mutant NSCLC cells. CI - Copyright (c) 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Sun, Shibo AU - Sun S AD - School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, China. FAU - Zhang, Yue AU - Zhang Y AD - School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, China. FAU - Xu, Weiping AU - Xu W AD - School of Ocean Science and Technology (OST) & Key Laboratory of Industrial Ecology and Environmental Engineering of MOE, Dalian University of Technology, Panjin 124221, China. FAU - Yang, Rui AU - Yang R AD - School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, China. FAU - Yang, Yijia AU - Yang Y AD - School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, China. FAU - Guo, Jianli AU - Guo J AD - School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, China. FAU - Ma, Qiang AU - Ma Q AD - Chinese Academy of Inspection and Quarantine, Beijing 100176, China. FAU - Ma, Kun AU - Ma K AD - School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, China. FAU - Zhang, Jie AU - Zhang J AD - Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United States. FAU - Xu, Jianqiang AU - Xu J AD - School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, China. Electronic address: Jianqiang.Xu@dlut.edu.cn. LA - eng PT - Journal Article DEP - 20211223 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (BAY-876) RN - 0 (Glucose Transporter Type 1) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Naphthoquinones) RN - 0 (Pyrazoles) RN - 0 (Quinolines) RN - 0 (Reactive Oxygen Species) RN - 0CH9049VIS (Selenocysteine) RN - EC 1.8.1.9 (Thioredoxin Reductase 1) RN - YAS4TBQ4OQ (plumbagin) SB - IM MH - Animals MH - Carcinoma, Non-Small-Cell Lung/genetics/pathology MH - Cell Line, Tumor MH - Cell Survival/drug effects MH - Glucose Transporter Type 1/*antagonists & inhibitors MH - Humans MH - Kelch-Like ECH-Associated Protein 1/*genetics MH - Lung Neoplasms/genetics/pathology MH - NF-E2-Related Factor 2/drug effects MH - Naphthoquinones/*pharmacology MH - Pyrazoles/*pharmacology MH - Quinolines/*pharmacology MH - Rats MH - Reactive Oxygen Species/metabolism MH - Selenocysteine/metabolism MH - Thioredoxin Reductase 1/*pharmacology OTO - NOTNLM OT - Glucose limitation OT - KEAP1 mutation OT - Naphthoquinone OT - Non-small cell lung cancer (NSCLC) OT - Plumbagin OT - Thioredoxin reductase 1 EDAT- 2021/12/27 06:00 MHDA- 2022/03/22 06:00 CRDT- 2021/12/26 20:55 PHST- 2021/11/01 00:00 [received] PHST- 2021/12/07 00:00 [revised] PHST- 2021/12/13 00:00 [accepted] PHST- 2021/12/27 06:00 [pubmed] PHST- 2022/03/22 06:00 [medline] PHST- 2021/12/26 20:55 [entrez] AID - S0753-3322(21)01333-0 [pii] AID - 10.1016/j.biopha.2021.112546 [doi] PST - ppublish SO - Biomed Pharmacother. 2022 Feb;146:112546. doi: 10.1016/j.biopha.2021.112546. Epub 2021 Dec 23.