IkappaBalpha independent induction of NF-kappaB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells.
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.
Watanabe
Mariko
M
Department of Hematology, School of Medicine, Kitasato University, Kitasato, Sagamihara, Kanagawa, Japan.
Dewan
Md Zahidunnabi
MZ
Taira
Miyako
M
Shoda
Momoko
M
Honda
Mitsuo
M
Sata
Testutaro
T
Higashihara
Masaaki
M
Kadin
Marshall E
ME
Watanabe
Toshiki
T
Yamamoto
Naoki
N
Umezawa
Kazuo
K
Horie
Ryouichi
R
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
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