title: Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation.
abstract: The KEAP1-NRF2 system regulates the cellular defence against oxidative and xenobiotic stresses. NRF2 is a transcription factor that activates the expression of cytoprotective genes encoding antioxidative, detoxifying and metabolic enzymes as well as transporters. Under normal conditions, KEAP1 represses NRF2 activity by degrading the NRF2 protein. When cells are exposed to stresses, KEAP1 stops promoting NRF2 degradation, and NRF2 rapidly accumulates and activates the transcription of target genes. Constitutive accumulation of NRF2 via a variety of mechanisms that disrupt KEAP1-mediated NRF2 degradation has been observed in various cancer types. Constitutive NRF2 accumulation confers cancer cells with a proliferative advantage as well as resistance to anti-cancer drugs and radiotherapies. To suppress the chemo- and radio-resistance of cancer cells caused by NRF2 accumulation, we conducted high-throughput chemical library screening for NRF2 inhibitors and identified febrifugine derivatives. We found that application of the less-toxic derivative halofuginone in a low dose range rapidly reduced NRF2 protein levels. Halofuginone induced a cellular amino acid starvation response that repressed global protein synthesis and rapidly depleted NRF2. Halofuginone treatment ameliorated the resistance of NRF2-addicted cancer cells to anti-cancer drugs both in vitro and in vivo. These results provide preclinical proof-of-concept evidence for halofuginone as an NRF2 inhibitor applicable to treatment of chemo- and radio-resistant forms of cancer.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsuchida
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Applied Biochemistry and Food Science, Saga University, Saga 840-8502, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Asaka
authors.initials: A
authors.lastname: Ojima
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Nadine
authors.initials: N
authors.lastname: Keleku-Lukwete
authors.affiliation: Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.affiliation: Division of Medical Biochemistry, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Otsuki
authors.affiliation: Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Electronic address: suzukimikiko@med.tohoku.ac.jp.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan. Electronic address: masiyamamoto@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010880:Piperidines; D052999:Quinazolinones; C010176:halofuginone; D002945:Cisplatin
keywords: Cancer; Halofuginone; Inhibitor; KEAP1; NRF2