IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Constitutive nuclear factor kappa B (NF-kappa B) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kappa B has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kappa B level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kappa B activation through I kappa B kinase activation in not only H-RS cell lines with wild-type I kappa B alpha, but also in those with Ik kappa B alpha mutations and lacking wild-type I kappa B alpha. Thus, both constitutive and inducible NF-kappa B are potential targets to treat HL. We also present the data that indicate the involvement of I kappa B alpha in NF-kappa B induction by topoisomerase inhibitors. A new NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kappa B activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gc null (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NF kappa B. Results of this study suggest that both constitutive and inducible NF-kappa B are molecular targets of DHMEQ in the treatment of HL. The results also indicate that I kappa B alpha is involved in NF-kappa B activation in H-RS cells and I kappa B alpha substitutes for I kappa B alpha in H-RS cells lacking wild type I kappa B alpha.