Chronic lymphocytic leukemia (CLL) is a low-grade lymphoid malignancy incurable with conventional modalities of chemotherapy. Strong and constitutive nuclear factor kappa B (NF-κB) activation is a characteristic of CLL cells. We examined the effects of a new NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on CLL cells. Dehydroxymethylepoxyquinomicin completely abrogated constitutive NF-κB activity and induced apoptosis of CLL cells. Apoptosis induced by DHMEQ was accompanied by downregulation of NF-κB-dependent antiapoptotic genes: c-IAP, Bfl-1, Bcl-XL and c-FLIP. Dehydroxymethylepoxyquinomicin also inhibited NF-κB induced by CD40 and enhanced fludarabine-mediated apoptosis of CLL cells. Results of this study suggest that inhibition of constitutive and inducible NF-κB by DHMEQ in combination with fludarabine is a promising strategy for the treatment of CLL.
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We thank Professor Marshall E Kadin, Harvard Medical School, for critical comments on the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from Japanese Society for Promotion of Science and Integrative Research Program of the Graduate School of Medical Sciences, Kitasato University to R Horie.
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Horie, R., Watanabe, M., Okamura, T. et al. DHMEQ, a new NF-κB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells. Leukemia 20, 800–806 (2006). https://doi.org/10.1038/sj.leu.2404167
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