title: [Reversal effect of LBH589 alone or in combination with bortezomib on drug-resistance in myeloid leukemia and its mechanism].
abstract: OBJECTIVE
  To investigate reversal effect of histone deacetylase inhibitor LBH589 alone or in combination with proteasome inhibitor bortezomib on drug resistance in acute myeloid leukemia (AML) and its mechanism.
  
  
  METHODS
  Ex vivo cultures of HL-60/ADM cells and fresh refractory AML cells were treated with LBH589, bortezomib or their combination at varying concentrations. Proliferation capacity, apoptosis rate and reversal of drug resistance were evaluated by MTT assay, dual staining of Hoechst 33342 and Annexin VFITC/PI by flow cytometry, and adriamycin uptake rate with proliferation inhibition, respectively. The change of signal pathway at protein level was analyzed by Western blot.
  
  
  RESULTS
  Synergistic cytotoxicity was observed in the combination treatment with LBH589 and bortezomib against HL-60/ADM cells, as well as the fresh AML cells, the most powerful synergy being observed at 21 nmol/L LBH589 plus 12 nmol/L bortezomib, with CI values of 0.531 and 0.498, respectively by Calcusyn software analysis. Moreover, the accumulation of adriamycin in HL-60/ADM cells was increased more in combination treatment [(64.81 +/- 3.69)%] than in either LBH589 [(28.96 +/- 2.52)%] or bortezomib [(37.29 +/- 3.71)%] alone (P < 0.05), and so did the uptake rate of adriamycin being (64.81 +/- 3.69)%, (28.96 +/- 2.52)% and (37.29 +/- 3.71)% respectively (P < 0.05). The combination treatment induced multiple apoptotic molecules co-action and intracellular drug accumulation contributed to the synergistic cytotoxicity, including caspase activation, PARP cleavage, XIAP downregulation, p53-dependent suppression of Bcl-2 and MRP1 expression via the inhibition of phosphoinositide 3-kinase (PI3K)/Akt/nuclear factor-kappaB (NF-kappaB) signaling pathway.
  
  
  CONCLUSIONS
  Combination treatment of drug resistant AML cells with LBH589 and bortezomib produces a synergistic effect of in creating sensitivity to chemotherapy. The mechanism may be mainly resulted from inhibition of PI3K/ Akt/NF-kappaB signaling pathway.
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 China.
authors.forename: Xue-Jie
authors.initials: XJ
authors.lastname: Jiang
authors.forename: Fan-Yi
authors.initials: FY
authors.lastname: Meng
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Zhou
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Fu-Qun
authors.initials: FQ
authors.lastname: Wu
authors.forename: Kai-Kai
authors.initials: KK
authors.lastname: Huang
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Wang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism; D000077767:Panobinostat; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D006877:Hydroxamic Acids; D007211:Indoles; D011719:Pyrazines; D000069286:Bortezomib; D000077767:Panobinostat