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Inhibition of NF-κB essentially contributes to arsenic-induced apoptosis

Item Type:Article
Title:Inhibition of NF-κB essentially contributes to arsenic-induced apoptosis
Creators Name:Mathas, S. and Lietz, A. and Janz, M. and Hinz, M. and Jundt, F. and Scheidereit, C. and Bommert, K. and Doerken, B.
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-{kappa}B (NF-{kapppa}B) in arsenic-induced apoptosis. Arsenic rapidly down-regulated constitutive I{kapa}B kinase (IKK) as well as NF-{kappa}B activity and induced apoptosis in HRS cell lines containing functional I{kappa}B proteins. In these cell lines, apoptosis was blocked by inhibition of caspase-8 and caspase-3-like activity. Furthermore, arsenic treatment down-regulated NF-{kappa}B target genes, including tumor necrosis factor-{alpha} receptor-associated factor 1 (TRAF1), c-IAP2, interleukin-13 (IL-13), and CCR7. In contrast, cell lines with mutated, functionally inactive I{kappa}B proteins or with a weak constitutive IKK/NF-{kappa}B activity showed no alteration of the NF-{kappa}B activity and were resistant to arsenic-induced apoptosis. A direct role of the NF-{kappa}B pathway in arsenic-induced apoptosis is shown by transient overexpression of NF-{kappa}B-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-{kappa}B inhibition. We conclude that inhibition of NF-{kappa}B contributes to arsenic-induced apoptosis. Furthermore, pharmacologic inhibition of the IKK/NF-{kappa}B activity might be a powerful treatment option for Hodgkin lymphoma.
Keywords:Apoptosis, Arsenic, Arsenicals, Arsenites, Cultured Tumor Cells, Down-Regulation, Gene Expression Profiling, Heterologous Transplantation, Hodgkin Disease, I-{kappa} B Kinase, NF-{kappa} B, Oxides, Protein-Serine-Threonine Kinases, Reed-Sternberg Cells, SCID Mice, Sodium Compounds, Animals, Mice
Publisher:American Society of Hematology
Page Range:1028-1034
Date:1 August 2003
Official Publication:https://doi.org/10.1182/blood-2002-04-1154
PubMed:View item in PubMed

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