Abstract
We investigated if deguelin, a naturally occurring rotenoid, was able to inhibit nuclear factor kappa B (NF-κB)-binding protein (IκBα) expression and to induce apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro. Deguelin-induced cell death in the majority of B-CLL cells and was found to be more toxic toward B-CLL cells than to the normal mononuclear or B-cells, suggesting selectivity towards the malignant cells. Deguelin was found to reduce IκBα protein expression, and thus interacts with the NFκB pathway. The induced apoptosis was characterized by processing of caspase-9 and -3 and poly-(ADP)-ribose-polymerase cleavage. Exposure of B-CLL cells to deguelin resulted in Bcl2-associated protein (Bax) conformational changes and downregulation of the key survival protein myeloid cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. Deguelin retained its ability to induce apoptosis in B-CLL cells in the presence of interleukin-4, a pro-survival cytokine in B-CLL, and when cultured with 50% human serum. These data indicate that deguelin is able to induce apoptosis in B-CLL cells in the presence of pro-survival signals and thus merits further investigation for clinical application either as a single agent or in combination with other anticancer agents.
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Acknowledgements
This work was supported by grants from the Research-fund of Ghent University (Belgium). BG is a PhD student, supported by the Research-fund of Ghent University (Belgium). B Vanhoecke was supported by the ‘Vlaamse Liga tegen Kanker’ (E Verschueren Fonds) and by the ‘FOD volksgezondheid FYTOES project’ (grant number B/06950/01).
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Geeraerts, B., Vanhoecke, B., Vanden Berghe, W. et al. Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro. Leukemia 21, 1610–1618 (2007). https://doi.org/10.1038/sj.leu.2404788
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DOI: https://doi.org/10.1038/sj.leu.2404788
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