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MLN120B, a Novel IB Kinase ß Inhibitor, Blocks Multiple Myeloma Cell Growth In vitro and In vivo

Authors' Affiliations: ¹ Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts and ² Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

Requests for reprints: Kenneth C. Anderson, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-2144; Fax: 617-632-2140; E-mail: kenneth_anderson{at}dfci.harvard.edu.

Purpose: The purpose of this study is to delineate the biological significance of IB kinase (IKK) ß inhibition in multiple myeloma cells in the context of bone marrow stromal cells (BMSC) using a novel IKKß inhibitor MLN120B.

Experimental Design: Growth-inhibitory effect of MLN120B in multiple myeloma cells in the presence of cytokines [interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-1)], conventional agents (dexamethasone, melphalan, and doxorubicin), or BMSC was assessed in vitro. In vivo anti-multiple myeloma activity of MLN120B was evaluated in severe combined immunodeficient (SCID)–hu model.

Results: MLN120B inhibits both baseline and tumor necrosis factor-–induced nuclear factor-B activation, associated with down-regulation of IB and p65 nuclear factor-B phosphorylation. MLN120B triggers 25% to 90% growth inhibition in a dose-dependent fashion in multiple myeloma cell lines and significantly augments tumor necrosis factor-–induced cytotoxicity in MM.1S cells. MLN120B augments growth inhibition triggered by doxorubicin and melphalan in both RPMI 8226 and IL-6-dependent INA6 cell lines. Neither IL-6 nor IGF-1 overcomes the growth-inhibitory effect of MLN120B. MLN120B inhibits constitutive IL-6 secretion by BMSCs by 70% to 80% without affecting viability. Importantly, MLN120B almost completely blocks stimulation of MM.1S, U266, and INA6 cell growth, as well as IL-6 secretion from BMSCs, induced by multiple myeloma cell adherence to BMSCs. MLN120B overcomes the protective effect of BMSCs against conventional (dexamethasone) therapy.

Conclusions: Our data show that the novel IKKß inhibitor MLN120B induces growth inhibition of multiple myeloma cells in SCID-hu mouse model. These studies provide the framework for clinical evaluation of MLN120B, alone and in combined therapies, trials of these novel agents to improve patient outcome in multiple myeloma.

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