title: Platelet-derived growth factor receptor beta inhibition increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity: imatinib and TRAIL dual therapy.
abstract: BACKGROUND
  There is a crucial need for better therapeutic approaches for the treatment of Ewing sarcoma (EWS). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in EWS cells in vitro. However, in vivo, acquired resistance to TRAIL is a major limiting factor. Platelet-derived growth factor receptor-beta (PDGFR-beta) is highly expressed on EWS cells. Thus, the authors evaluated whether PDGFR-beta blockade could sensitize EWS cells to TRAIL-induced apoptosis in vitro and in vivo.
  
  
  METHODS
  The effect of combined imatinib mesylate (Gleevec) and TRAIL on EWS cell growth and apoptosis was tested in vitro. Stable PDGFR-beta knockdown in EWS cells was achieved by short-hairpin RNA transduction, and TRAIL sensitivity of these cells was measured. Expression of death receptors was measured by fluorescence-activated cell-sorting (FACS) analysis, and caspase 8 activity was evaluated by Western blot analysis. An orthotopic human xenograft model of EWS growth and spontaneous metastasis in nude mice was used to assess the in vivo affect of combined imatinib mesylate and TRAIL.
  
  
  RESULTS
  Imatinib mesylate induced a significant TRAIL proapoptotic effect in EWS cells in vitro. Specific PDGFR-beta silencing in EWS cells enhanced the effects of TRAIL, possibly through an increase in the expression of death receptors 4 and 5. The combination of imatinib mesylate and TRAIL significantly inhibited the growth of primary tumors and decreased the incidence of spontaneous EWS pulmonary metastasis compared with either drug alone.
  
  
  CONCLUSIONS
  PDGFR-beta blockade combined with TRAIL resulted in antihuman EWS activity in vitro and in vivo, suggesting the possibility that combining these treatments will improve anti-EWS therapy.
authors.affiliation: Department of Pediatrics-Research, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Deendayal
authors.initials: D
authors.lastname: Mandal
authors.forename: Suizhau
authors.initials: S
authors.lastname: Wang
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.forename: Andrea
authors.initials: A
authors.lastname: Hayes-Jordan
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010879:Piperazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta