bsc2118 and Multiple-Myeloma

Introduction of bortezomib, the first generation of proteasome inhibitor, has significantly improved the median overall survival of patients with multiple myeloma (MM). However, the dose-limiting adverse events and acquired drug resistance limit its long-term usage. Here, we report in vitro and in vivo anti-MM activity of the irreversible proteasome inhibitor BSc2118. BSc2118 inhibited the chymotrypsin-like (CT-L) proteasome activity, accompanied by accumulation of ubiquitinated proteins. BSc2118 suppressed tumor cell growth through induction of G2/M phase arrest and induced apoptosis via activation of the apoptotic signaling cascade, in association with up-regulation of p53 and p21. Importantly, BSc2118 was active in vitro against MM cells' acquired bortezomib resistance. Of note, BSc2118 also displayed a novel anti-angiogenesis activity both in vitro and in vivo. Lastly, BSc2118 exhibited a broader safety dose range and higher anti-tumor efficacy in vivo in a human MM xenograft mouse model, compared to bortezomib. Together, these findings indicate the in vitro and in vivo anti-MM activities of BSc2118 through induction of cell cycle arrest and apoptosis, as well as inhibition of tumor angiogenesis. They also suggest that BSc2118 might, at least in vitro, partially overcome acquired bortezomib resistance, likely associated with inhibition of autophagy.

Topics: Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Butanes; Caspases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Enzyme Activation; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Neovascularization, Pathologic; NF-kappa B; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Tumor Suppressor Protein p53; Up-Regulation; Xenograft Model Antitumor Assays

The ubiquitin-proteasome system emerged as a new therapeutic target in cancer treatment. The purpose of this study was to elucidate the effects of the novel proteasome inhibitor BSc2118 on t(4;14) positive and negative multiple myeloma (MM) cells and normal peripheral blood mononuclear cells (PBMNC).. Human MM cell lines OPM-2, RPMI-8226, and U266 and primary MM cells from bone marrow aspirates were exposed to BSc2118. Cytotoxicity levels were evaluated using the MTT-test. BSc2118-induced apoptosis was analyzed by annexin-V assay. Further methods used included proteasomal activity determination, cell cycle analysis, western blot, and transcription factor assays.. In OPM-2, RPMI-8226, U266 cell lines and primary MM cells, BSc2118 caused dose-dependent growth inhibitory effects. After 48 h, dose-dependent apoptosis occurred both in cell lines and primary myeloma cells irrespective of t(4;14). A significant G2-M cell cycle arrest occurred after 24 h. Furthermore, we observed a marked inhibition of intracellular proteasome activity, an increase in intracellular p21 levels, and an inhibition of NF-kappaB activation. The toxicity against PBMNC remained low, suggesting a broad therapeutic range of this agent.. Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development.

Topics: Antineoplastic Agents; Apoptosis; Bone Marrow Examination; Butanes; Cell Cycle; Cell Line, Tumor; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Leukocytes, Mononuclear; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Translocation, Genetic