Platelet-derived growth factor receptor beta inhibition increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity: imatinib and TRAIL dual therapy.
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.
Wang
Yongxin
Y
Department of Pediatrics-Research, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mandal
Deendayal
D
Wang
Suizhau
S
Kleinerman
Eugenie S
ES
Pollock
Raphael E
RE
Lev
Dina
D
Hayes-Jordan
Andrea
A
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
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