1. ¹Department of Hematology, School of Medicine, Kitasato University, Kitasato, Sagamihara, Kanagawa, Japan
2. ²Department of Molecular Virology, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
3. ³AIDS Research Center, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo, Japan
4. ⁴Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan
5. ⁵Department of Pathology, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo, Japan
6. ⁶Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA
7. ⁷Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, Japan

Correspondence: Dr R Horie, MD, PhD, Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. E-mail: rhorie@med.kitasato-u.ac.jp; Dr N Yamamoto, MD, PhD, Department of Molecular Virology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: yamamoto.mmb@tmd.ac.jp

^*These authors contributed equally to this work.

Received 20 May 2006; Revised 25 November 2006; Accepted 16 December 2006; Published online 19 February 2007.

Abstract

Constitutive nuclear factor B (NF-B) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-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-B level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-B activation through IB kinase activation in not only H-RS cell lines with wild-type IB, but also in those with IB mutations and lacking wild-type IB. Thus, both constitutive and inducible NF-B are potential targets to treat HL. We also present the data that indicate the involvement of IB in NF-B induction by topoisomerase inhibitors. A new NF-B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-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/c^null (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NF-B. Results of this study suggest that both constitutive and inducible NF-B are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IB is involved in NF-B activation in H-RS cells and IB substitutes for IB in H-RS cells lacking wild-type IB.