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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    ABSTRACT: Inhibition of the proteasome offers many therapeutic possibilities in inflammation as well as in neoplastic diseases. However, clinical use of proteasome inhibitors is limited by the development of resistance or severe side effects. In our study we characterized the anti-tumor properties of the novel proteasome inhibitor BSc2118. The sensitivity of tumor lines to BSc2118 was analyzed in comparison to bortezomib using crystal violet staining in order to assess cell viability. The In Vivo distribution of BSc2118 in mouse tissues was tracked by a fluorescent-modified form of BSc2118 (BSc2118-FL) and visualized by confocal microscopy. Inhibition of the 20S proteasome was monitored both in cultured cell lines and in mice, respectively. Finally, safety and efficacy of BSc2118 was evaluated in a mouse melanoma model. BSc2118 inhibits proliferation of different tumor cell lines with a similar potency as compared with bortezomib. Systemic administration of BSc2118 in mice is well tolerated, even when given in a dose of 60 mg/kg body weight. After systemic injection of BSc2118 or bortezomib similar proteasome inhibition patterns are observed within the murine organs. Detection of BSc2118-FL revealed correlation of distribution pattern of BSc2118 with inhibition of proteasomal activity in cells or mouse tissues. Finally, administration of BSc2118 in a mouse melanoma model shows significant local anti-tumor effects. Concluding, BSc2118 represents a novel low-toxic agent that might be alternatively used for known proteasome inhibitors in anti-cancer treatment.
    Translational oncology 10/2014; 7(5):570–579. DOI:10.1016/j.tranon.2014.07.002 · 2.88 Impact Factor
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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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    ABSTRACT: Despite marked improvement in the prognosis of patients with nonmetastatic Ewing sarcoma (ES), the outcome for patients with recurrent or metastatic disease remains poor. Insight into key biologic processes in ES could provide new therapeutic targets. The particular biologic feature of ES, the fusion of the EWS gene with a member of the ETS family of genes, is present in >95% of cases. The EWS-ETS chimeric protein leads to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways. Recent research has identified cooperating mutations important for ES tumorigenesis. This paper provides a summary of the latest research in ES and discusses potential novel targets for therapy.
    05/2012; 2012(10):609439. DOI:10.5402/2012/609439
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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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    ABSTRACT: Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) has been reported to specifically induce malignant cell death being relatively nontoxic to normal cells. Since its identification 15 years ago, the antitumor activity and therapeutic value of TRAIL have been extensively studied. Five receptors quickly emerged, two of them being able to induce programmed cell death in tumor cells. This review takes a comprehensive look at this ligand and its receptors, and its potential role in primary bone tumors (osteosarcoma and Ewing's sarcoma) therapy. The main limit of clinical use of TRAIL being the innate or acquired resistance mechanisms, different possibilities to sensitize resistant cells are discussed in this review, together with the impact of bone microenvironment in the regulation of TRAIL activity.
    American Journal of Cancer Research 01/2012; 2(1):45-64. · 4.17 Impact Factor
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