title: Inhibition of NF-kappaB essentially contributes to arsenic-induced apoptosis.
abstract: Arsenic can induce apoptosis and is an efficient drug for the treatment of acute promyelocytic leukemia. Currently, clinical studies are investigating arsenic as a therapeutic agent for a variety of malignancies. In this study, Hodgkin/Reed-Sternberg (HRS) cell lines served as model systems to characterize the role of nuclear factor-kappaB (NF-kappaB) in arsenic-induced apoptosis. Arsenic rapidly down-regulated constitutive IkappaB kinase (IKK) as well as NF-kappaB activity and induced apoptosis in HRS cell lines containing functional IkappaB proteins. In these cell lines, apoptosis was blocked by inhibition of caspase-8 and caspase-3-like activity. Furthermore, arsenic treatment down-regulated NF-kappaB target genes, including tumor necrosis factor-alphareceptor-associated factor 1 (TRAF1), c-IAP2, interleukin-13 (IL-13), and CCR7. In contrast, cell lines with mutated, functionally inactive IkappaB proteins or with a weak constitutive IKK/NF-kappaB activity showed no alteration of the NF-kappaB activity and were resistant to arsenic-induced apoptosis. A direct role of the NF-kappaB pathway in arsenic-induced apoptosis is shown by transient overexpression of NF-kappaB-p65 in L540Cy HRS cells, which protected the cells from arsenic-induced apoptosis. In addition, treatment of NOD/SCID mice with arsenic trioxide induced a dramatic reduction of xenotransplanted L540Cy Hodgkin tumors concomitant with NF-kappaB inhibition. We conclude that inhibition of NF-kappaB contributes to arsenic-induced apoptosis. Furthermore, pharmacologic inhibition of the IKK/NF-kappaB activity might be a powerful treatment option for Hodgkin lymphoma.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, FG Dörken, Robert-Rössle-Str. 10, D-13125 Berlin, Germany. mathas@rrk-berlin.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
authors.forename: Andreas
authors.initials: A
authors.lastname: Lietz
authors.forename: Martin
authors.initials: M
authors.lastname: Janz
authors.forename: Michael
authors.initials: M
authors.lastname: Hinz
authors.forename: Franziska
authors.initials: F
authors.lastname: Jundt
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
authors.forename: Kurt
authors.initials: K
authors.lastname: Bommert
authors.forename: Bernd
authors.initials: B
authors.lastname: Dorken
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010087:Oxides / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016539:Reed-Sternberg Cells / Q000187:drug effects / Q000473:pathology*; D017670:Sodium Compounds / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D001152:Arsenicals; D018053:Arsenites; D016328:NF-kappa B; D010087:Oxides; D017670:Sodium Compounds; C017947:sodium arsenite; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D001151:Arsenic; D000077237:Arsenic Trioxide