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Canonical Nuclear Factor B Pathway Inhibition Blocks Myeloma Cell Growth and Induces Apoptosis in Strong Synergy with TRAIL

Authors' Affiliations: ¹ INSERM, UMR 601, ² Université de Nantes, Faculté de Médecine, ³ Department of Clinical Hematology, CHR Nantes, Nantes, France; ⁴ Centre de Lutte contre le Cancer Rene Gauducheau, Saint Herblain, France; and ⁵ Merck Serono International SA, Geneva, Switzerland

Requests for reprints: Sophie Barillé-Nion, UMR 601, 9 quai Moncousu, Nantes F-44093, France. Phone: 33-24008-4766; Fax: 33-24008-4778; E-mail: sbarille{at}nantes.inserm.fr.

Purpose: Intrinsic activation of nuclear factor B (NF-B) characterizes various hematologic malignancies. In this study, we specifically address the role of NF-B blockade in mediated antimyeloma activity using the IB kinase-2 pharmacologic inhibitor, AS602868.

Experimental Design: Human myeloma cell lines (n = 16) and primary myeloma cells (n = 10) were tested for their sensitivity to AS602868 in terms of proliferation and apoptosis. Both in vitro and in vivo experiments were conducted. Functional mechanisms regarding the apoptotic pathways triggered by AS602868 were studied. The potential proapoptotic synergy between AS602868 and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) was also evaluated.

Results: Our results show that AS602868 efficiently targeted the canonical NF-B pathway in myeloma cells and potently inhibited their growth in inducing apoptosis through Bax and caspase-3 activation. AS602868 also induced apoptosis in primary myeloma cells even in the presence of bone marrow mononuclear cells. Moreover, the IB kinase-2 inhibitor targeted the paracrine effect on the bone marrow environment. Indeed, it decreased the intrinsic and myeloma-induced secretion of interleukin-6 from bone marrow stromal cells. In addition, AS602868 inhibited myeloma cell growth in the MM.1S xenograft myeloma model. Of particular interest, AS602868 strongly increased myeloma sensitivity to TRAIL in blocking TRAIL-induced NF-B activation and in decreasing the expression of antiapoptotic proteins such as cFLIP and cIAP-1/2.

Conclusions: Taken together, our data point out the interest to inhibit the canonical NF-B pathway in myeloma and clearly encourage clinical evaluation of novel therapies based on targeting NF-B, especially in combination with TRAIL.

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