title: [The Hsp90 inhibitor FW-04-806 suppresses Bcr/Abl-mediated growth of leukemia cells by inhibiting proliferation and inducing apoptosis].
abstract: OBJECTIVE
  To investigate the antitumor efficacy and mechanism of HSP90 inhibitor FW-04-806 against Bcr/Abl(+) leukemia K562 and HL60 cells and their mechanisms of action.
  
  
  METHODS
  MTT assay was used to assess the proliferation-inhibiting effect of FW-04-806. Cell cycle was analyzed with propidium iodide by flow cytometry. Cell apoptosis was determined using the FITC mV apoptosis detection kit. Western blot was applied to reveal the protein expression of related proliferative and apoptotic signaling pathways. The changes of mitochondrial membrane potential were detected by flow cytometry. Protein-protein interactions was shown by co-immunoprecipitation. The level of mRNA was assessed by real-time RT-PCR.
  
  
  RESULTS
  FW-04-806 obviously inhibited cell proliferation in the HL60, K562 and HL60/Bcr-Abl cell lines, with an IC50 of (30.89 ± 0.12) µmol/L, (9.76 ± 0.19) µmol/L and (8.03 ± 0.26) µmol/L, respectively (P<0.001). Compared with the vehicle group, the two increasing doses of FW-04-806 showed inhibition of tumor growth at a rate of (17.40 ± 0.34)% and (34.33 ± 5.00)%, respectively, in the K562 cell line groups (P=0.003), and (18.90 ± 1.45)% and (35.60 ± 3.55)% (P=0.001) in the HL60/Bcr-Abl cell line groups. FW-04-806 dissociated Hsp90/Cdc37 chaperon/co-chaperon complex, followed by degradation of the Hsp90 proteins through proteasome pathway without affecting mRNA expression. FW-04-806 induced apoptosis and led to G2/M arrest.
  
  
  CONCLUSIONS
  Our findings indicate that FW-04-806 displays potential antitumor effect by suppressing the proliferation and apoptosis in Bcr/Abl(+) leukemia cells in vivo.
authors.affiliation: Biological Pharmaceutical Laboratory of Fujian Medical University, Fuzhou 350004, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Kong
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Pinrong
authors.initials: P
authors.lastname: Cao
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Luo
authors.forename: Bingying
authors.initials: B
authors.lastname: She
authors.affiliation: Email: xjh@mail.fjmu.edu.cn.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Email: yeminkobe@hotmail.com.
authors.forename: Min
authors.initials: M
authors.lastname: Ye
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D010080:Oxazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018841:HSP90 Heat-Shock Proteins; D010080:Oxazoles; D012333:RNA, Messenger; C022800:conglobatin; D016044:Fusion Proteins, bcr-abl