Abstract
Nuclear factor-κB (NF-κB) 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-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB 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-κB 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.
Highlights
The compound IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), which is a novel inhibitor of IkB phosphorylation, was shown to induce apoptosis in human mast cells with constitutively activated c-kit receptors and was suggested to have therapeutic activity.12 IMD-0354 inhibits the IkB kinases (IKK)-induced phosphorylation of IkBa and protects it from undergoing degradation, which in turn results in the inhibition of nuclear factor-kB (NF-kB) activation
We investigated the effect of IMD-0354 in chronic lymphocytic leukemia (CLL) cells in vitro by performing Annexin V stainings and a nonclonogenic cytotoxicity assay
To determine whether IMD-0354 is capable of inducing apoptosis in CLL cells in vitro, cells from 20 CLL patients were incubated in the presence and absence of IMD-0354
Summary
The compound IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), which is a novel inhibitor of IkB phosphorylation, was shown to induce apoptosis in human mast cells with constitutively activated c-kit receptors and was suggested to have therapeutic activity. IMD-0354 inhibits the IKK-induced phosphorylation of IkBa and protects it from undergoing degradation, which in turn results in the inhibition of NF-kB activation. The compound IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), which is a novel inhibitor of IkB phosphorylation, was shown to induce apoptosis in human mast cells with constitutively activated c-kit receptors and was suggested to have therapeutic activity.. IMD-0354 inhibits the IKK-induced phosphorylation of IkBa and protects it from undergoing degradation, which in turn results in the inhibition of NF-kB activation. We investigated the effect of IMD-0354 in CLL cells in vitro by performing Annexin V stainings and a nonclonogenic cytotoxicity assay. We investigated the effect of IMD-0354 treatment on gene expression of different pro- and antiapoptotic genes. Our data clearly show that IMD-3054 can induce apoptosis of CLL cells directly by inhibiting the NF-kB pathway and should be further investigated as a new potential drug in CLL treatment
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