Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma

Sally A. Hunsucker, Valeria Magarotto, Deborah J. Kuhn, Steven M. Kornblau, Michael Wang, Donna M. Weber, Sheeba K. Thomas, Jatin J. Shah, Peter M. Voorhees, Hong Xie, Mark Cornfeld, Jeffrey A. Nemeth, Robert Z. Orlowski

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase-3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies.

Original languageEnglish
Pages (from-to)579-592
Number of pages14
JournalBritish Journal of Haematology
Volume152
Issue number5
DOIs
StatePublished - Mar 2011
Externally publishedYes

Keywords

  • Akt
  • Interleukin-6
  • Melphalan
  • Multiple myeloma
  • Siltuximab

Fingerprint

Dive into the research topics of 'Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma'. Together they form a unique fingerprint.

Cite this