The NF-kappaB inhibitor LC-1 has single agent activity in multiple myeloma cells and synergizes with bortezomib.
Multiple myeloma remains incurable with conventional therapeutics. Thus, new treatments for this condition are clearly required. In this study we evaluated the novel NF-kappaB inhibitor LC-1 in multiple myeloma cell lines and plasma cells derived from multiple myeloma patients. LC-1 was cytotoxic to multiple myeloma cell lines H929, U266, and JJN3, and induced apoptosis in a dose-dependent manner with an overall LD(50) of 3.6 micromol/L (+/-1.8) after 48 hours in culture. Primary multiple myeloma cells, identified by CD38 and CD138 positivity, had a mean LD(50) for LC-1 of 4.9 micromol/L (+/-1.6); normal bone marrow cells were significantly less sensitive to the cytotoxic effects of LC-1 (P = 0.0002). Treatment of multiple myeloma cell lines with LC-1 resulted in decreased nuclear localization of the NF-kappaB subunit Rel A and the inhibition of NF-kappaB target genes. In addition, LC-1 showed synergy with melphalan, bortezomib, and doxorubicin (combination indices of 0.72, 0.61, and 0.78, respectively), and was more effective when cells were cultured on fibronectin. These data show that LC-1 has activity in multiple myeloma cell lines and primary multiple myeloma cells, and its ability to inhibit NF-kappaB seems important for its cytotoxic effects. Furthermore, LC-1-induced transcriptional suppression of survivin and MCL1 provides a potential explanation for its synergy with conventional agents.
Walsby
Elisabeth J
EJ
Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Pratt
Guy
G
Hewamana
Saman
S
Crooks
Peter A
PA
Burnett
Alan K
AK
Fegan
Chris
C
Pepper
Chris
C
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001897:Boronic Acids; D000069286:Bortezomib; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011719:Pyrazines; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D051996:Transcription Factor RelA / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; C524858:LC-1 compound; D016328:NF-kappa B; D011719:Pyrazines; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; D000069286:Bortezomib; D004247:DNA; D053148:Caspase 3