nsc-680410 and Multiple-Myeloma

Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1alpha (Hif-1alpha) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1alpha and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1alpha-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1alpha as a novel molecular target in MM and add another facet to anti-MM drug activity.

Topics: Adamantane; Angiogenesis Inhibitors; Animals; Blotting, Western; Cell Line, Tumor; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Hydroquinones; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Mice; Mice, Nude; Multiple Myeloma; Neovascularization, Pathologic; Proto-Oncogene Proteins c-myc; Vascular Endothelial Growth Factor A

Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors.

Topics: Adamantane; Apoptosis; Benzamides; Boronic Acids; Bortezomib; Caspase Inhibitors; Caspases; Cell Growth Processes; Dexamethasone; Humans; Hydroquinones; Imatinib Mesylate; Leukemia, Erythroblastic, Acute; Melphalan; Multiple Myeloma; Piperazines; Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins c-jun; Pyrazines; Pyrimidines; Transfection; Up-Regulation