MLN120B, a Novel IκB Kinase β Inhibitor, Blocks Multiple Myeloma Cell Growth In vitro and In vivo

Abstract

The purpose of this study is to delineate the biological significance of IkappaB kinase (IKK) beta inhibition in multiple myeloma cells in the context of bone marrow stromal cells (BMSC) using a novel IKKbeta inhibitor MLN120B. 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. MLN120B inhibits both baseline and tumor necrosis factor-alpha-induced nuclear factor-kappaB activation, associated with down-regulation of IkappaBalpha and p65 nuclear factor-kappaB phosphorylation. MLN120B triggers 25% to 90% growth inhibition in a dose-dependent fashion in multiple myeloma cell lines and significantly augments tumor necrosis factor-alpha-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. Our data show that the novel IKKbeta 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.