Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma
| العنوان: | Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma |
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| المؤلفون: | Deborah J. Kuhn, Jeffrey A. Nemeth, Peter M. Voorhees, Mohamed H. Zaki, Robert Corringham, Sally A. Hunsucker, George W. Small, John S. Strader, Qing Chen, Robert Z. Orlowski |
| المصدر: | Clinical Cancer Research. 13:6469-6478 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | STAT3 Transcription Factor, Cancer Research, Stromal cell, Myeloid, Cell, Antineoplastic Agents, Apoptosis, Bone Marrow Cells, DNA Fragmentation, Biology, Bortezomib, immune system diseases, hemic and lymphatic diseases, medicine, Humans, HSP70 Heat-Shock Proteins, Multiple myeloma, Interleukin-6, Antibodies, Monoclonal, medicine.disease, Boronic Acids, Gene Expression Regulation, Neoplastic, STAT1 Transcription Factor, medicine.anatomical_structure, Oncology, Proteasome, Drug Resistance, Neoplasm, Pyrazines, Proteasome inhibitor, Cancer research, Immunotherapy, Syndecan-1, Bone marrow, Multiple Myeloma, Signal Transduction, medicine.drug |
| الوصف: | Purpose: Inhibition of the proteasome leads to the activation of survival pathways in addition to those that promote cell death. We hypothesized that down-regulation of interleukin-6 (IL-6) signaling using the monoclonal antibody CNTO 328 would enhance the antitumor activity of the proteasome inhibitor bortezomib in multiple myeloma by attenuating inducible chemoresistance.Experimental Design: The cytotoxicity of bortezomib, CNTO 328, and the combination, along with the associated molecular changes, was assessed in IL-6–dependent and IL-6–independent multiple myeloma cell lines, both in suspension and in the presence of bone marrow stromal cells and in patient-derived myeloma samples.Results: Treatment of IL-6–dependent and IL-6–independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion. This effect was additive to synergistic and was preserved in the presence of bone marrow stromal cells and in CD138+ myeloma samples derived from patients with relative clinical resistance to bortezomib. CNTO 328 potentiated bortezomib-mediated activation of caspase-8 and caspase-9 and the common downstream effector caspase-3; attenuated bortezomib-mediated induction of antiapoptotic heat shock protein-70, which correlated with down-regulation of phosphorylated signal transducer and activator of transcription-1; and inhibited bortezomib-mediated accumulation of myeloid cell leukemia-1, an effect that was associated with down-regulation of phosphorylated signal transducer and activator of transcription-3.Conclusions: Taken together, our results provide a strong preclinical rationale for the clinical development of the bortezomib/CNTO 328 combination for patients with myeloma. |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::97d80fcc7d270795afdc7ae89e3e0f8fTest https://doi.org/10.1158/1078-0432.ccr-07-1293Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....97d80fcc7d270795afdc7ae89e3e0f8f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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