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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    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 · 3.40 Impact Factor
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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. · 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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    ABSTRACT: Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. Although most patients respond to the initial therapy when presenting with advanced disease, only 10-15% maintain a complete response following first-line therapy. Recurrence defines incurable disease in most cases. Despite improvements with conventional chemotherapy combinations, the overall cure rate remained mostly stable over the years. Increased long-term survival in OC patients will only be achieved through a comprehensive understanding of the basic mechanisms of tumor cell resistance. Such knowledge will translate into the development of new targeted strategies. In addition, because OC is considered to be a heterogeneous group of diseases with distinct gene expression profiles, it is likely that different approaches to treatment for distinct sub-types will be required to optimize response. One of the new promising anti-cancer therapies is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL has the ability to selectively induce apoptosis in tumor cells with little toxicity to normal cells. Death receptor ligands such as TRAIL rely on the activation of the apoptotic signaling pathway to destroy tumor cells. TRAIL induces the formation of a pro-apoptotic death-inducing signaling complex (DISC) via its death receptors, TRAIL receptor 1 (TRAIL R1) and TRAIL receptor 2 (TRAIL R2). The formation of the DISC activates caspase-8 which requires further signal amplification through the mitochondrial pathway for an efficient activation of effector caspases in OC cells. The initial enthusiasm for TRAIL has been hampered by accumulating data demonstrating TRAIL resistance in various tumor types including OC cells. There is, therefore, a need to identify markers of TRAIL resistance, which could represent new hits for targeted therapy that will enhance TRAIL efficacy. In addition, the identification of patients that are more likely to respond to TRAIL therapy would be highly desirable. In this review, we discuss the different molecular and cellular mechanisms leading to TRAIL resistance in OC. In particular, we address the mechanisms involved in intrinsic, acquired and environment-mediated TRAIL resistance, and their potential implication in the clinical outcome.
    American Journal of Cancer Research 01/2012; 2(1):75-92. · 3.97 Impact Factor
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