Proteasome inhibitor Bortezomib induces cell-cycle arrest and apoptosis in cell lines derived from Ewing’s sarcoma family of tumors and synergizes with TRAIL

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Cancer biology & therapy (Impact Factor: 3.07). 05/2008; 7(4):603-8. DOI: 10.4161/cbt.7.4.5564
Source: PubMed


Bortezomib (VELCADE), formerly known as PS-341, is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo anti-tumor activity. Bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma. In this report, we examined the sensitivity of cell lines derived from Ewing's sarcoma-family of tumors (ESFT) to Bortezomib. Five ESFT-derived cell lines, TC-71, TC-32, SK-N-MC, A4573 and GRIMES, were highly sensitive to Bortezomib (IC(50) = 20 to 50 nM), and underwent cell cycle arrest and apoptosis following drug treatment. Bortezomib-induced apoptosis was associated with activation of caspase 3, cleavage of PARP and induction of p27 and p21 expression. Moreover, Bortezomib exhibited synergistic activity against the TC-71 and TC-32 cell lines when combined with TRAIL. Our results suggest that Bortezomib might be a useful agent for treatment of ESFT, when used alone or in combination with TRAIL.

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    • "Therefore, we analyzed the potential for BSc2118 usage in different application forms to be considered for proteasome inhibition. These typically include anti-tumor effects based on cell cycle arrest and on inducing apoptosis [34] [35]. Although Bortezomib was developed and approved for therapy of multiple myeloma and mantle cell lymphoma only, therapeutic potential for other tumors was investigated within the last years as well [37]. "
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    • "Another therapy showing synergistic effect in two ES cell lines was treatment with histone deacetylase inhibitors and TRAIL [38]. Similarly, application of TRAIL and the proteasome inhibitor bortezomib to ES cell lines resulted in cell cycle arrest and apoptosis [39]. In a mouse model, combination treatment with TRAIL and the tyrosine kinase inhibitor imatinib reduced both the volume of primary tumours as well as pulmonary metastases possibly due to imatinib-induced enhancement of NK-cell sensitivity to IL-2 or IL-12 leading to increased IFN-γ release and stimulation of TRAIL-downstream pathways. "
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    • "However, the proteasome inhibitor MG132 sensitized these cell lines to TRAIL. Another more recent study confirm these results showing that bortezomib, a novel proteasome inhibitor, exhibited synergistic activity against two Ewing's sarcoma cell lines when combined with TRAIL [107]. Another therapeutic combination to overcome TRAIL resistance was demonstrated by Wang and coll. "
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