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: Yongxin Wang, Deendayal Mandal, Suizhau Wang, Eugenie S Kleinerman, Raphael E Pollock, Dina Lev, Andrea Hayes-Jordan
• Journal: Cancer (Cancer) Vol. 116 Issue 16 Pg. 3892-902 (Aug 15 2010) ISSN: 0008-543X [Print] United States
• PMID: 20564078 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 American Cancer Society.

Chemical References

• Benzamides
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• TNF-Related Apoptosis-Inducing Ligand
• Imatinib Mesylate
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Benzamides
• Humans
• Imatinib Mesylate
• Mice
• Mice, Nude
• Neoplasm Metastasis (prevention & control)
• Piperazines (administration & dosage)
• Protein Kinase Inhibitors (administration & dosage)
• Pyrimidines (administration & dosage)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors)
• Sarcoma, Ewing (drug therapy, pathology)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage)
• Tumor Cells, Cultured