The NF-KB Inhibitor LC-1 Has Single Agent Activity in Multiple Myeloma Cells and Synergizes with Bortezomib

Research output: Contribution to journalArticle

Authors

  • EJ Walsby
  • S Hewamana
  • PA Crooks
  • AK Burnett
  • C Fegan
  • C Pepper

Colleges, School and Institutes

Abstract

Multiple myeloma remains incurable with conventional therapeutics. Thus, new treatments for this condition are clearly required. In this study we evaluated the novel NF-kappa B 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 LD50 of 3.6 mu mol/L (+/- 1.8) after 48 hours in culture. Primary multiple myeloma cells, identified by CD38 and CD138 positivity, had a mean LD50 for LC-1 of 4.9 mu mol/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-kappa B subunit Rel A and the inhibition of NF-kappa B 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-.B 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. Mol Cancer Ther; 9(6); 1574-82. (C)2010 AACR.

Details

Original languageEnglish
Pages (from-to)1574-1582
Number of pages9
JournalMolecular Cancer Therapeutics
Volume9
Issue number6
Publication statusPublished - 1 Jun 2010