title: Effects of the HIF1 inhibitor, echinomycin, on growth and NOTCH signalling in leukaemia cells.
abstract: OBJECTIVE
  To examine the effects of echinomycin, a compound that inhibits DNA-binding activity of hypoxia-inducible factor-1 (HIF1), on leukaemia cell growth.
  
  
  METHODS
  Three acute myeloid leukaemia cell lines and three T-lymphoblastic leukaemia cell lines were cultured with echinomycin. Cell growth, mRNA and protein expression levels were examined by WST-1 assay, reverse-transcription polymerase chain reaction and immunoblotting, respectively.
  
  
  RESULTS
  HIF1α protein was expressed in all cell lines under normoxia. Treatment with echinomycin suppressed cell growth and induced apoptosis in association with decreased mRNA expression of HIF1 targets, glucose transporter-1 (GLUT1) and B-cell CLL/lymphoma-2 (BCL2). Echinomycin also suppressed the protein expression of NOTCH1, cleaved NOTCH1, v-myc myelocytomatosis viral oncogene homolog (MYC), v-akt murine thymoma viral oncogene homolog-1 (AKT), phosphorylated AKT, mechanistic target of rapamycin (mTOR), and phosphorylated mTOR and increased that of cleaved caspase-3 in some cell lines.
  
  
  CONCLUSIONS
  Echinomycin suppresses leukaemia cell growth in association with reduced NOTCH1 expression. This is the first report to show that HIF inhibitor treatment suppresses NOTCH1 signalling. HIF inhibitors could be novel candidates for a molecular-targeted therapy against leukaemia.
authors.affiliation: Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo 113-8519, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yonekura
authors.forename: Mai
authors.initials: M
authors.lastname: Itoh
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okuhashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Aya
authors.initials: A
authors.lastname: Ono
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nara
authors.forename: Shuji
authors.initials: S
authors.lastname: Tohda
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004448:Echinomycin / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D004448:Echinomycin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: HIF; Jurkat cells; Leukaemia; NB4; NOTCH; echinomycin