Fighting drug-resistant lung cancer by induction of NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated ferroptosis

Jie Yu; Bingling Zhong; Lin Zhao; Ying Hou; Nana Ai; Jin-Jian Lu; Wei Ge; Xiuping Chen

doi:10.1016/j.drup.2023.100977

Fighting drug-resistant lung cancer by induction of NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated ferroptosis

Drug Resist Updat. 2023 Sep:70:100977. doi: 10.1016/j.drup.2023.100977. Epub 2023 Jun 2.

Authors

Jie Yu¹, Bingling Zhong², Lin Zhao², Ying Hou², Nana Ai³, Jin-Jian Lu², Wei Ge³, Xiuping Chen⁴

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao Special Administrative Region of China; School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao Special Administrative Region of China.
³ Department of Biomedical Sciences and Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region of China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao Special Administrative Region of China; Department of Pharmaceutical Sciences, Faculty of Health Scien ces, University of Macau, Taipa, Macao Special Administrative Region of China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao Special Administrative Region of China. Electronic address: xpchen@um.edu.mo.

PMID: 37321064
DOI: 10.1016/j.drup.2023.100977

Abstract

Drug resistance is a major challenge in cancer treatment. The substrates of NAD(P)H:quinone oxidoreductase 1 (NQO1) show a promising anticancer effect in clinical trials. We previously identified a natural NQO1 substrate 2-methoxy-6-acetyl-7-methyljuglone (MAM) with a potent anticancer effect. The present study was designed to explore the efficacy of MAM in fighting against drug-resistant non-small cell lung cancer (NSCLC). The anticancer effect of MAM was evaluated in cisplatin-resistant A549 and AZD9291-resistant H1975 cells. The interaction of MAM with NQO1 was measured by cellular thermal shift assay and drug affinity responsive target stability assay. The NQO1 activity and expression were measured using NQO1 recombinant protein, Western blotting, and immunofluorescence staining assay. The roles of NQO1 were examined by NQO1 inhibitor, small interfering RNA (siRNA), and short hairpin RNA (shRNA). The roles of reactive oxygen species (ROS), labile iron pool (LIP), and lipid peroxidation were determined. MAM induced significant cell death in drug-resistant cells with similar potency to that of parental cells, which were completely abolished by NQO1 inhibitor, NQO1 siRNA, and iron chelators. MAM activates and binds to NQO1, which triggers ROS generation, LIP increase, and lipid peroxidation. MAM significantly suppressed tumor growth in the tumor xenograft zebrafish model. These results showed that MAM induced ferroptosis by targeting NQO1 in drug-resistant NSCLC cells. Our findings provided a novel therapeutic strategy for fighting against drug resistance by induction of NQO1-mediated ferroptosis.

Keywords: Drug-resistance; Ferroptosis; Lung cancer; MAM; NQO1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung* / drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm
Ferroptosis*
Humans
Lung Neoplasms* / drug therapy
NAD / therapeutic use
NAD(P)H Dehydrogenase (Quinone)* / genetics
NAD(P)H Dehydrogenase (Quinone)* / metabolism
RNA, Small Interfering / genetics
Reactive Oxygen Species / metabolism
Zebrafish / genetics
Zebrafish / metabolism

Substances

NAD
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, human
Reactive Oxygen Species
RNA, Small Interfering