2. Academic Validation
  3. Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells

Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells

  • Oncotarget. 2017 Jan 31;8(5):7625-7636. doi: 10.18632/oncotarget.13825.
JinFeng Zhang 1 2,  Le Su 1,  Qing Ye 3,  ShangLi Zhang 1,  HsiangFu Kung 1 4,  Fan Jiang 3,  GuoSheng Jiang 5,  JunYing Miao 1 3,  BaoXiang Zhao 6
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
  • 2 School of Municipal and Environmental Engineering, Shandong Jianzhu University, Jinan 250101, China.
  • 3 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
  • 4 Institute of Pathology and Southwest Cancer Center, Third Military Medical University, Chongqing, 400038, China.
  • 5 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.
  • 6 Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
PMID: 28032588 DOI: 10.18632/oncotarget.13825
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.

Keywords

Bcl-2; Nrf2 inhibitors; acute myeloid leukemia; apoptosis; pyrazolyl hydroxamic acid derivatives.

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