Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma.
Clin Cancer Res. 2007 Nov 1;13(21):6469-6478
Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS, Corringham RE, Zaki MH, Nemeth JA, Orlowski RZ.
Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, and Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina and Centocor, Inc., Horsham, Pennsylvania.
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. |
