title: LGP1, A histone deacetylase inhibitor analogue of FR235222, sensitizes promyelocytic leukaemia U937 cells to TRAIL-mediated apoptosis.
abstract: BACKGROUND
  It has been shown that chemo-therapeutic agents, such as histone deacetylase inhibitors (HDACi), are able to increase TRAIL-induced apoptosis in many types of cancer. In the present study, we investigated the effects of the novel HDACi LGP1, a new simplified analogue of FR235222, in human leukaemia U937 cells resistant to TRAIL-induced apoptosis.
  
  
  METHODS
  U937 cells were incubated with TRAIL/LGP1 for 24 h and apoptosis was evaluated using flow cytometric assay and cleavage of caspase-3 and (PARP) by Western blot. Western blot analysis was also used to detect the expression of p21, p27, (NF-kappaB), Bcl-2 and the levels of H4 histone acetylation. Finally, flow cytometry was used to monitor the enhancement of TRAIL-receptor levels.
  
  
  RESULTS
  Treatment with LGP1 caused accumulation of acetylated histone H4 and G(1) cycle arrest accompanied by increase of p21. The compound was also able to sensitize U937 cells to TRAIL-induced apoptosis through multiple mechanisms: (i) activation of caspase-3 and cleavage of PARP; (ii) induction of p21 and p27; (iii) cleavage of NF-kappaB and down-regulation of Bcl-2. Finally, LGP1 induced up-regulation of TRAIL-R1 receptor expression.
  
  
  CONCLUSIONS
  These results demonstrate that U937 cells can be effectively killed by a combination treatment of subtoxic doses of LGP1 and TRAIL.
authors.affiliation: Department of Pharmaceutical Science, University of Salerno, Via Ponte Don Melillo 84084 Fisciano (Salerno), Italy. apetrella@unisa.it
authors.forename: Cosimo Walter
authors.initials: CW
authors.lastname: D'Acunto
authors.forename: Anna
authors.initials: A
authors.lastname: Carratù
authors.forename: Manuela
authors.initials: M
authors.lastname: Rodriquez
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
authors.forename: Luca
authors.initials: L
authors.lastname: Parente
authors.forename: Antonello
authors.initials: A
authors.lastname: Petrella
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation; D016193:G1 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C549428:LGP1 compound; D010456:Peptides, Cyclic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D020169:Caspases