title: BH3 mimetic ABT-737 induces apoptosis in CD34+acute myeloid leukemia cells and shows synergistic effect with conventional chemotherapeutic drugs.
abstract: OBJECTIVE
  Acute myeloid leukemia (AML) is an immunophenotypically heterogenous malignant disease. The early immature CD34+AML cell subpopulation is frequently impervious to intensive chemotherapy, making them largely responsible for relapse of AML. CD34+AML cells have higher level of Bcl-2 protein expression than the CD34-subpopulation. As such, development of drugs that specifically target the Bcl-2 may have the potential to eliminate immature CD34+AML progenitor cells and provide therapeutic benefit. In this work, we made an attempt to investigate the cytotoxic effect of a novel Bcl-2 family inhibitor, ABT-737, on CD34+AML cell lines (KG1a and Kasumi-1) as well as CD34+primary AML cells.
  
  
  METHODS
  Primary human CD34+cells were isolated from bone marrow mononuclear cells using CD34 MicroBead kit. The growth inhibitory effect was measured by cell counting kit-8. Apoptosis was analyzed by annexin V/PI assays. Protein expression was determined by Western blotting analysis.
  
  
  RESULTS
  Inhibition of Bcl-2 by ABT-737 effectively inhibited growth and induced apoptosis in CD34+AML cell lines and CD34+primary AML cells without affecting CD34+normal hematopoietic cells. Furthermore, Western blot analysis showed that ABT-737 induced apoptosis associated with caspase-3 activation and poly ADP-ribose polymerase (PARP) degradation. Finally, ABT-737 synergistically enhanced the cytotoxic effect of cytarabine and daunorubicin in CD34+AML cells.
  
  
  CONCLUSIONS
  Taken together, these findings indicate that ABT-737 may offer as a promising molecular targeting agent in CD34+AML.
authors.affiliation: Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Rao
authors.affiliation: Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China.
authors.forename: Rong-Yan
authors.initials: RY
authors.lastname: Zhang
authors.affiliation: Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Zhou
authors.affiliation: Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China.
authors.forename: Guo-An
authors.initials: GA
authors.lastname: Chen
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D019254:Genes, bcl-2 / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism*; D055815:Young Adult
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides
keywords: ABT-737; Bcl-2; acute myeloid leukemia; apoptosis