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Platelet-derived growth factor receptor β inhibition increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity
Imatinib and TRAIL dual therapy
Article first published online: 24 MAY 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 16, pages 3892–3902, 15 August 2010
How to Cite
Wang, Y., Mandal, D., Wang, S., Kleinerman, E. S., Pollock, R. E., Lev, D. and Hayes-Jordan, A. (2010), Platelet-derived growth factor receptor β inhibition increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity. Cancer, 116: 3892–3902. doi: 10.1002/cncr.25107
- Issue published online: 4 AUG 2010
- Article first published online: 24 MAY 2010
- Manuscript Accepted: 27 AUG 2009
- Manuscript Revised: 17 AUG 2009
- Manuscript Received: 29 APR 2009
- Ewing sarcoma;
- tumor necrosis factor-related apoptosis-inducing ligand;
- platelet-derived growth factor receptor β;
- intranasal therapy;
- orthotopic animal model
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-β (PDGFR-β) is highly expressed on EWS cells. Thus, the authors evaluated whether PDGFR-β blockade could sensitize EWS cells to TRAIL-induced apoptosis in vitro and in vivo.
The effect of combined imatinib mesylate (Gleevec) and TRAIL on EWS cell growth and apoptosis was tested in vitro. Stable PDGFR-β 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.
Imatinib mesylate induced a significant TRAIL proapoptotic effect in EWS cells in vitro. Specific PDGFR-β 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.
PDGFR-β 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. Cancer 2010. © 2010 American Cancer Society.