title: Suppression of NRF2-ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells.
abstract: Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the antioxidant response element (ARE)-dependent transcription, plays a pivotal role in chemical detoxification in normal and tumor cells. Consistent with previous findings that NRF2-ARE contributes to chemotherapeutic resistance of cancer cells, we found that stable knockdown of NRF2 by lentiviral shRNA in human acute monocytic leukemia (AML) THP-1 cells enhanced the cytotoxicity of several chemotherapeutic agents, including arsenic trioxide (As2O3), etoposide and doxorubicin. Using an ARE-luciferase reporter expressed in several human and mouse cells, we identified a set of compounds, including isonicotinic acid amides, isoniazid and ethionamide, that inhibited NRF2-ARE activity. Treatment of THP-1 cells with ethionamide, for instance, significantly reduced mRNA expression of multiple ARE-driven genes under either basal or As2O3-challenged conditions. As determined by cell viability and cell cycle, suppression of NRF2-ARE by ethionamide also significantly enhanced susceptibility of THP-1 and U937 cells to As2O3-induced cytotoxicity. In THP-1 cells, the sensitizing effect of ethionamide on As2O3-induced cytotoxicity was highly dependent on NRF2. To our knowledge, the present study is the first to demonstrate that ethionamide suppresses NRF2-ARE signaling and disrupts the transcriptional network of the antioxidant response in AML cells, leading to sensitization to chemotherapeutic agents.
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA; Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: School of Public Health, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA; Key Laboratory of the Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.affiliation: School of Public Health, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang, China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA; Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Dong
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Key Laboratory of the Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Qu
authors.affiliation: Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
authors.affiliation: Unilever, Safety & Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Unilever, Safety & Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA.
authors.forename: Bud
authors.initials: B
authors.lastname: Nelson
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Clewell
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA.
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.affiliation: School of Public Health, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang, China; The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC, USA. Electronic address: jpi@mail.cmu.edu.cn.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D061745:Antioxidant Response Elements / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005000:Ethionamide / Q000627:therapeutic use / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use / Q000633:toxicity; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D005000:Ethionamide; D007538:Isoniazid
keywords: Arsenic trioxide; Chemotherapeutic resistance; Cytotoxicity; Ethionamide; Isoniazid; Leukemia; NRF2