The novel NF-kappa B inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia
2011 (English)In: Blood Cancer Journal, ISSN 2044-5385, Vol. 1, e12- p.Article in journal (Refereed) Published
Nuclear factor-kappa B (NF-kappa B) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-kappa B inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of I kappa B alpha by IkB kinases, thus preventing NF-kappa B release. In this study, we investigated if IMD-0354 can inhibit NF-kappa B activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-kappa B were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-kappa B in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo.
Place, publisher, year, edition, pages
2011. Vol. 1, e12- p.
chronic lymphocytic leukemia, IMD-0354, nuclear factor-kappa B, apoptosis, drug sensitivity
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-168436DOI: 10.1038/bcj.2011.9ISI: 000298815400006OAI: oai:DiVA.org:uu-168436DiVA: diva2:496965