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.
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ABSTRACT: IL-6 and TNF α were significantly increased in the bone marrow aspirate samples of patients with active multiple myeloma (MM) compared to those of normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNF α than those with MM in plateau phase. TNF α increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNF α promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNF α treatments induce MEK and AKT phosphorylation. TNF α -stimulated IL-6 production was abolished by inhibition of JAK2 and IKK β or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNF α increased phosphorylation of STAT3 (ser727) including c-Myc and cyclin D1. Three different types of JAK inhibitors decreased the activation of the previously mentioned pathways. In conclusion, blockage of JAK/STAT-mediated NF- κ B activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNF α -mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma.BioMed Research International 09/2013; 2013:580135. DOI:10.1155/2013/580135 · 2.71 Impact Factor
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ABSTRACT: Nuclear Factor kappaB (NF-kappaB) transcription factors are central regulators of lymphocyte proliferation, survival and development. Although normally subject to tight control, constitutive activation of NF-kappaB promotes inappropriate lymphocyte survival and proliferation, and is recognised as key pathological feature in various lymphoid malignancies. Inhibition of NF-kappaB may be an attractive therapeutic approach in these diseases. This review focuses on the mechanisms and functional consequences of NF-kappaB activation in lymphoid malignancies and potential therapeutic strategies for inhibition of NF-kappaB.British Journal of Haematology 07/2008; 143(1):3-15. DOI:10.1111/j.1365-2141.2008.07284.x · 4.96 Impact Factor
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ABSTRACT: It is known that the cytoplasmic zinc finger protein A20 functionally dampens inflammatory signals and apoptosis via inhibition of NF-kappaB activation and biochemically acts as a unique ubiquitin-modifying protein with deubiquitinating activity and ubiquitin ligase activity. However, the molecular mechanisms of A20-modulated signal transduction that influence normal immune responses or tumor immunity have not been fully elucidated. Using a yeast two-hybrid system to search for proteins interacting with A20, we identified one novel binding protein, Ymer. Ymer, which has been reported to be highly phosphorylated on tyrosine residues via EGF stimulation, bound to lysine (K)-63-linked polyubiquitin chain on receptor-interacting serine/threonine-protein kinase 1 (RIP1), which is essential for NF-kappaB signaling in collaboration with A20. A luciferase assay showed that NF-kappaB signaling was down-regulated by overexpression of Ymer, whereas knock-down of Ymer up-regulated NF-kappaB signaling even without stimulation. These findings demonstrate that Ymer is likely to be a negative regulator for the NF-kappaB signaling pathway.Biochimica et Biophysica Acta 06/2008; 1783(5):826-37. DOI:10.1016/j.bbamcr.2007.09.006 · 4.66 Impact Factor