BSc2118 is a novel proteasome inhibitor with activity against multiple myeloma.

Abstract

OBJECTIVES:

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).

METHODS:

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.

RESULTS:

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.

CONCLUSION:

Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development.

• Authors: Jan Sterz, Christian Jakob, Ulrike Kuckelkorn, Ulrike Heider, Maren Mieth, Lorenz Kleeberg, Martin Kaiser, Peter-M Kloetzel, Orhan Sezer, Ivana von Metzler
• Journal: European journal of haematology (Eur J Haematol) Vol. 85 Issue 2 Pg. 99-107 (Aug 2010) ISSN: 1600-0609 [Electronic] England
• PMID: 20374272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BSc2118
• Butanes
• Oligopeptides
• Proteasome Inhibitors

Topics

• Antineoplastic Agents
• Apoptosis (drug effects)
• Bone Marrow Examination
• Butanes (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cells, Cultured
• Dose-Response Relationship, Drug
• Humans
• Leukocytes, Mononuclear (drug effects)
• Multiple Myeloma (drug therapy, pathology)
• Oligopeptides (pharmacology)
• Proteasome Inhibitors
• Translocation, Genetic