Premium
Targeted inhibition of interleukin‐6 with CNTO 328 sensitizes pre‐clinical models of multiple myeloma to dexamethasone‐mediated cell death
Author(s) -
Voorhees Peter M.,
Chen Qing,
Small George W.,
Kuhn Deborah J.,
Hunsucker Sally A.,
Nemeth Jeffrey A.,
Orlowski Robert Z.
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07647.x
Subject(s) - bortezomib , apoptosis , annexin a5 , cancer research , medicine , stromal cell , programmed cell death , dexamethasone , annexin , multiple myeloma , immunology , biology , flow cytometry , biochemistry
Summary 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.