title: IkappaBalpha independent induction of NF-kappaB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells.
abstract: Constitutive nuclear factor kappaB (NF-kappaB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kappaB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kappaB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kappaB activation through IkappaB kinase activation in not only H-RS cell lines with wild-type IkappaBalpha, but also in those with IkappaBalpha mutations and lacking wild-type IkappaBalpha. Thus, both constitutive and inducible NF-kappaB are potential targets to treat HL. We also present the data that indicate the involvement of IkappaBbeta in NF-kappaB induction by topoisomerase inhibitors. A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kappaB 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/gammac(null) (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NF-kappaB. Results of this study suggest that both constitutive and inducible NF-kappaB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkappaBbeta is involved in NF-kappaB activation in H-RS cells and IkappaBbeta substitutes for IkappaBalpha in H-RS cells lacking wild-type IkappaBalpha.
authors.affiliation: Department of Hematology, School of Medicine, Kitasato University, Kitasato, Sagamihara, Kanagawa, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Md Zahidunnabi
authors.initials: MZ
authors.lastname: Dewan
authors.forename: Miyako
authors.initials: M
authors.lastname: Taira
authors.forename: Momoko
authors.initials: M
authors.lastname: Shoda
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Honda
authors.forename: Testutaro
authors.initials: T
authors.lastname: Sata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Higashihara
authors.forename: Marshall E
authors.initials: ME
authors.lastname: Kadin
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Ryouichi
authors.initials: R
authors.lastname: Horie
mesh_terms: D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003512:Cyclohexanones / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D006689:Hodgkin Disease; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009368:Neoplasm Transplantation; D016539:Reed-Sternberg Cells / Q000378:metabolism*; D059003:Topoisomerase Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D059003:Topoisomerase Inhibitors; C464444:dehydroxymethylepoxyquinomicin; D000072000:NF-KappaB Inhibitor alpha; D005047:Etoposide; D051550:I-kappa B Kinase; D020169:Caspases; D003630:Daunorubicin