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: Mariko Watanabe, Md Zahidunnabi Dewan, Miyako Taira, Momoko Shoda, Mitsuo Honda, Testutaro Sata, Masaaki Higashihara, Marshall E Kadin, Toshiki Watanabe, Naoki Yamamoto, Kazuo Umezawa, Ryouichi Horie
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 87 Issue 4 Pg. 372-82 (Apr 2007) ISSN: 0023-6837 [Print] United States
• PMID: 17310217 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Cyclohexanones
• I kappa B beta protein
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Nfkbia protein, mouse
• Topoisomerase Inhibitors
• dehydroxymethylepoxyquinomicin
• NF-KappaB Inhibitor alpha
• Etoposide
• I-kappa B Kinase
• Caspases
• Daunorubicin

Topics

• Animals
• Apoptosis
• Benzamides (pharmacology)
• Caspases (metabolism)
• Cell Line
• Cyclohexanones (pharmacology)
• Daunorubicin (pharmacology)
• Enzyme Activation
• Etoposide (pharmacology)
• Hodgkin Disease
• Humans
• I-kappa B Kinase (metabolism)
• I-kappa B Proteins (genetics, metabolism, physiology)
• Leukocytes, Mononuclear (metabolism)
• Mice
• Mutation
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplasm Transplantation
• Reed-Sternberg Cells (metabolism)
• Topoisomerase Inhibitors
• Transplantation, Heterologous
• Tumor Cells, Cultured