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: Stephan Mathas, Andreas Lietz, Martin Janz, Michael Hinz, Franziska Jundt, Claus Scheidereit, Kurt Bommert, Bernd Dorken
• Journal: Blood (Blood) Vol. 102 Issue 3 Pg. 1028-34 (Aug 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12676792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arsenicals
• Arsenites
• NF-kappa B
• Oxides
• Sodium Compounds
• sodium arsenite
• Protein Serine-Threonine Kinases
• CHUK protein, human
• Chuk protein, mouse
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human
• Ikbkb protein, mouse
• Ikbke protein, mouse
• Arsenic
• Arsenic Trioxide

Topics

• Animals
• Apoptosis (drug effects)
• Arsenic (pharmacology)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Arsenites (pharmacology)
• Down-Regulation
• Gene Expression Profiling
• Hodgkin Disease (metabolism, pathology)
• Humans
• I-kappa B Kinase
• Mice
• Mice, SCID
• NF-kappa B (antagonists & inhibitors)
• Oxides (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Reed-Sternberg Cells (drug effects, pathology)
• Sodium Compounds (pharmacology)
• Transplantation, Heterologous
• Tumor Cells, Cultured