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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: 3.63). 05/2008; 7(4):603-8. DOI: 10.4161/cbt.7.4.5564
Source: PubMed

ABSTRACT 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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    • "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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    American Journal of Cancer Research 01/2012; 2(1):45-64. · 3.97 Impact Factor
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    • "These studies provided the basis for introducing proteasome inhibitors into the clinic, notably for multiple myelomas and mantle cell lymphomas [68] [69]. In addition, there is evidence in various tumor models that proteasome inhibitors enhance the sensitivity of tumor cells to TRAIL [70] [71] [72]. Several studies have shown that proteasome inhibitors enhance TRAIL-induced apoptosis in OC cell lines and primary OC cells [73] [74]. "
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