The NF- B inhibitor LC-1 has single agent activity in multiple myeloma cells and synergizes with bortezomib

Walsby, Elisabeth Jane ORCID: https://orcid.org/0000-0001-8523-5017, Pratt, G., Hewamana, Saman, Crooks, P. A., Burnett, Alan Kenneth, Fegan, Christopher Daniel. ORCID: https://orcid.org/0000-0001-9685-0621 and Pepper, Christopher John 2010. The NF- B inhibitor LC-1 has single agent activity in multiple myeloma cells and synergizes with bortezomib. Molecular Cancer Therapeutics 9 (6) , pp. 1574-1582. 10.1158/1535-7163.MCT-10-0104

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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-κB 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 μmol/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 μmol/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-κB subunit Rel A and the inhibition of NF-κB 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-κB 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Association for Cancer Research
ISSN:	1535-7163
Last Modified:	06 Feb 2023 15:33
URI:	https://orca.cardiff.ac.uk/id/eprint/27632

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