Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma.

@article{Voorhees2007InhibitionOI,
  title={Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma.},
  author={Peter Michael Voorhees and Qing Chen and Deborah J. Kuhn and George W. Small and Sally Anne Hunsucker and John S. Strader and Robert E Corringham and Mohamed H. Zaki and Jeffrey A. Nemeth and Robert Z. Orlowski},
  journal={Clinical cancer research : an official journal of the American Association for Cancer Research},
  year={2007},
  volume={13 21},
  pages={6469-78}
}
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… CONTINUE READING

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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 .
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 .
Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma .
Taken together , our results provide a strong preclinical rationale for the clinical development of the bortezomib / CNTO 328 combination for patients with myeloma .
Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma .
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 .
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 .
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 .
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 .
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 .
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 .
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