Combined Administration of Rituximab and ON 013105 Induces Apoptosis in Mantle Cell Lymphoma Cells and Reduces Tumor Burden in a Mouse Model of Mantle Cell Lymphoma
| Autor: | Ramesh Kumar, M. V. Ramana Reddy, Ashutosh Shrivastava, E. Premkumar Reddy, Paula M. Kuzontkoski, Evangelos Papadopoulos, Anil Prasad, Amanda M. Gillum, Jerome E. Groopman |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Gene Expression Apoptosis Lymphoma Mantle-Cell Styrenes Proto-Oncogene Proteins c-myc Antibodies Monoclonal Murine-Derived Mice Cyclin D1 In vivo Cell Line Tumor hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols medicine Animals Doxorubicin Sulfones Antibiotics Antineoplastic business.industry medicine.disease Mitochondria Tumor Burden Lymphoma Disease Models Animal Eukaryotic Initiation Factor-4E Oncology Monoclonal Immunology Cancer research Female Rituximab Mantle cell lymphoma business Protein Binding medicine.drug |
| Zdroj: | Clinical Cancer Research. 19:85-95 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma, and new therapeutic strategies are urgently needed. Experimental Design: The effects of ON 013105, a novel benzylstyryl sulfone kinase inhibitor, alone or with doxorubicin or rituximab, were examined in Granta 519 and Z138C cells. For in vivo studies, CB17/SCID mice were implanted subcutaneously with Z138C cells and treated with various combinations of ON 013105, doxorubicin, and rituximab. Tumor burden and body weight were monitored for 28 days. Results: ON 013105 induced mitochondria-mediated apoptosis in MCL cells. Death was preceded by translocation of tBid to the mitochondria and cytochrome c release. In addition, ON 013105–treated cells exhibited reduced levels of cyclin D1, c-Myc, Mcl-1, and Bcl-xL. Using nuclear magnetic resonance (NMR) spectroscopy, we showed specific binding of ON 013105 to eIF4E, a critical factor for the initiation of protein translation. We proffer that this drug–protein interaction preferentially prevents the translation of the aforementioned proteins and may be the mechanism by which ON 013105 induces apoptosis in MCL cells. Efficacy studies in a mouse xenograft model showed that ON 013105 inhibited MCL tumor growth and that combining ON 013105 with rituximab reduced tumor burden further with negligible unwanted effects. Conclusions: Our findings suggest that ON 013105, alone or in combination with rituximab, may be a potent therapeutic agent to treat MCLs. Clin Cancer Res; 19(1); 85–95. ©2012 AACR. |
| Databáze: | OpenAIRE |
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