title: An antiapoptotic Bcl-2 family protein index predicts the response of leukaemic cells to the pan-Bcl-2 inhibitor S1.
abstract: BACKGROUND
  Bcl-2-like members have been found to be inherently overexpressed in many types of haematologic malignancies. The small-molecule S1 is a BH3 mimetic and a triple inhibitor of Bcl-2, Mcl-1 and Bcl-XL.
  
  
  METHODS
  The lethal dose 50 (LD(50)) values of S1 in five leukaemic cell lines and 41 newly diagnosed leukaemia samples were tested. The levels of Bcl-2 family members and phosphorylated Bcl-2 were semiquantitatively measured by western blotting. The interactions between Bcl-2 family members were tested by co-immunoprecipitation. The correlation between the LD(50) and expression levels of Bcl-2 family members, alone or in combination, was analysed.
  
  
  RESULTS
  S1 exhibited variable sensitivity with LD(50) values ranging >2 logs in both established and primary leukaemic cells. The ratio of pBcl-2/(Bcl-2+Mcl-1) could predict the S1 response. Furthermore, we demonstrated that pBcl-2 antagonised S1 by sequestering the Bak and Bim proteins that were released from Mcl-1, andpBcl-2/Bak, pBcl-2/Bax and pBcl-2/Bim complexes cannot be disrupted by S1.
  
  
  CONCLUSIONS
  A predictive index was obtained for the novel BH3 mimetic S1. The shift of proapoptotic proteins from being complexed with Mcl-1 to being complexed with pBcl-2 was revealed for the first time, which is the mechanism underlying the index value described herein.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116024, China. zczhang@dlut.edu.cn
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Song
authors.forename: Z
authors.initials: Z
authors.lastname: Xue
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.forename: F
authors.initials: F
authors.lastname: Liang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Sheng
mesh_terms: D000073:Acenaphthenes / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein; D045744:Cell Line, Tumor; D019337:Hematologic Neoplasms / Q000378:metabolism; D006801:Humans; D007928:Lethal Dose 50; D007938:Leukemia / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D011758:Pyrroles / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C557101:8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile; D000073:Acenaphthenes; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D051020:bcl-X Protein
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