title: Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells.
abstract: Nuclear factor-erythroid 2-related factor 2 (Nrf2) is persistently activated in many human tumors including acute myeloid leukemia (AML). Therefore, inhibition of Nrf2 activity may be a promising target in leukemia therapy. Here, we used an antioxidant response element-luciferase reporter system to identify a novel pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole-5-carboxamide (4f), that inhibited Nrf2 activity. 4f had a profound growth-inhibitory effect on three AML cell lines, THP-1, HL-60 and U937, and a similar anti-growth effect in a chick embryo model. Moreover, flow cytometry of AML cells revealed increased apoptosis with 4f (10 μM) treatment for 48 h. The protein levels of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase were enhanced in all three AML cell types. Furthermore, Nrf2 protein level was downregulated by 4f. Upregulation of Nrf2 by tert-butylhydroquinone (tBHQ) or Nrf2 overexpression could ameliorate 4f-induced growth inhibition and apoptosis. Treatment with 4f reduced both B-cell lymphoma-2 (Bcl-2) expression and Bcl-2/Bcl-2-associated X protein (Bax) ratio, which indicated that 4f induced apoptosis, at least in part, via mitochondrial-dependent signaling. Therefore, as an Nrf2 inhibitor, the pyrazolyl hydroxamic acid derivative 4f may be a promising agent in AML therapy.
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.|School of Municipal and Environmental Engineering, Shandong Jianzhu University, Jinan 250101, China.
authors.forename: JinFeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: Le
authors.initials: L
authors.lastname: Su
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: ShangLi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.|Institute of Pathology and Southwest Cancer Center, Third Military Medical University, Chongqing, 400038, China.
authors.forename: HsiangFu
authors.initials: H
authors.lastname: Kung
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China.
authors.forename: GuoSheng
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.|Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: JunYing
authors.initials: J
authors.lastname: Miao
authors.affiliation: Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
authors.forename: BaoXiang
authors.initials: B
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000074084:THP-1 Cells; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011720:Pyrazoles
keywords: Bcl-2; Nrf2 inhibitors; acute myeloid leukemia; apoptosis; pyrazolyl hydroxamic acid derivatives