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Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma

Authors' Affiliations: ¹ Division of Hematology/Oncology, Department of Medicine, ² Lineberger Comprehensive Cancer Center, and ³ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina and ⁴ Centocor, Inc., Horsham, Pennsylvania

Requests for reprints: Peter M. Voorhees, The University of North Carolina at Chapel Hill, 3009 Old Clinic Building, Chapel Hill, NC 27599-7305. Phone: 919-966-5879; Fax: 919-966-6735; E-mail: Peter_Voorhees{at}med.unc.edu.

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.

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