title: Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death.
abstract: Interleukin (IL)-6-mediated signalling attenuates the anti-myeloma activity of glucocorticoids (GCs). We therefore sought to evaluate whether CNTO 328, an anti-IL-6 monoclonal antibody in clinical development, could enhance the apoptotic activity of dexamethasone (dex) in pre-clinical models of myeloma. CNTO 328 potently increased the cytotoxicity of dex in IL-6-dependent and -independent human myeloma cell lines (HMCLs), including a bortezomib-resistant HMCL. Isobologram analysis revealed that the CNTO 328/dex combination was highly synergistic. Addition of bortezomib to CNTO 328/dex further enhanced the cytotoxicity of the combination. Experiments with pharmacologic inhibitors revealed a role for the p44/42 mitogen-activated protein kinase pathway in IL-6-mediated GC resistance. Although CNTO 328 alone induced minimal cell death, it potentiated dex-mediated apoptosis, as evidenced by increased activation of caspases-8, -9 and -3, Annexin-V staining and DNA fragmentation. The ability of CNTO 328 to sensitize HMCLs to dex-mediated apoptosis was preserved in the presence of human bone marrow stromal cells. Importantly, the increased activity of the combination was also seen in plasma cells from patients with GC-resistant myeloma. Taken together, our data provide a strong rationale for the clinical development of the CNTO 328/dex regimen for patients with myeloma.
authors.affiliation: Department of Medicine, Division of Haematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7305, USA. Peter_Voorhees@med.unc.edu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Voorhees
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: George W
authors.initials: GW
authors.lastname: Small
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Kuhn
authors.forename: Sally A
authors.initials: SA
authors.lastname: Hunsucker
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nemeth
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski