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


CONCLUSIONS
Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development.
Sterz
Jan
J
Department of Hematology and Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany. sezer@charite.de; o.sezer@uke.de
Jakob
Christian
C
Kuckelkorn
Ulrike
U
Heider
Ulrike
U
Mieth
Maren
M
Kleeberg
Lorenz
L
Kaiser
Martin
M
Kloetzel
Peter-M
PM
Sezer
Orhan
O
von Metzler
Ivana
I
D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D001856:Bone Marrow Examination; D002073:Butanes / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; C513723:BSc2118; D002073:Butanes; D009842:Oligopeptides; D061988:Proteasome Inhibitors