title: HIF-1α inhibition by 2-methoxyestradiol induces cell death via activation of the mitochondrial apoptotic pathway in acute myeloid leukemia.
abstract: The bone marrow microenvironment plays an important role in the development and progression of AML. Leukemia stem cells are in a hypoxic condition, which induces the expression of HIF-1α. Aberrant activation of HIF-1α is implicated in the poor prognosis of patients with acute myeloid leukemia (AML). Herein, we investigated the expression of HIF-1α in AML and tested 2-methoxyestradiol (2ME2) as a candidate HIF-1α inhibitor for the treatment of AML. We found that HIF-1α was overexpressed in AML. HIF-1α suppression by 2ME2 significantly induced apoptosis of AML cells, and it outperformed traditional chemotherapy drugs such as cytarabine. At the same time, 2ME2 downregulated the transcriptional levels of VEGF, GLUT1 and HO-1 in cellular assays. Additionally, 2ME2 displayed antileukemia activity in bone marrow blasts from AML patients, but showed little effect on normal cells. 2ME2-induced activation of mitochondrial apoptotic pathway is mediated by reactive oxygen species (ROS), which decreased the slight effect of drug on normal cells. Our data show that supression of HIF-1α expression significantly reduced the survival of AML cell lines, suggesting that 2ME2 may represent a powerful therapeutic approach for patients with AML.
authors.affiliation: a Guizhou Medical University , Guiyang, Guizhou , China.
authors.forename: Nana
authors.initials: N
authors.lastname: Zhe
authors.affiliation: a Guizhou Medical University , Guiyang, Guizhou , China.|b Department of Pharmacy , Guizhou Medical University , Guiyang , Guizhou , China.
authors.forename: Shuya
authors.initials: S
authors.lastname: Chen
authors.affiliation: a Guizhou Medical University , Guiyang, Guizhou , China.|c Department of Pharmacy , Affiliated BaiYun Hospital of Guizhou Medical University , Guiyang , Guizhou , China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: a Guizhou Medical University , Guiyang, Guizhou , China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: a Guizhou Medical University , Guiyang, Guizhou , China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Lin
authors.affiliation: a Guizhou Medical University , Guiyang, Guizhou , China.
authors.forename: Meisheng
authors.initials: M
authors.lastname: Yu
authors.affiliation: a Guizhou Medical University , Guiyang, Guizhou , China.|b Department of Pharmacy , Guizhou Medical University , Guiyang , Guizhou , China.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Cheng
authors.affiliation: d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.|e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.|e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China.
authors.forename: Jishi
authors.initials: J
authors.lastname: Wang
mesh_terms: D000077584:2-Methoxyestradiol; D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol
keywords: 2-methoxyestradiaol; Hypoxia-inducible factor 1α; acute myeloid leukemia; hypoxia