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

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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–κB (NF-κB) in arsenic-induced apoptosis. Arsenic rapidly down-regulated constitutive IκB kinase (IKK) as well as NF-κB activity and induced apoptosis in HRS cell lines containing functional IκB proteins. In these cell lines, apoptosis was blocked by inhibition of caspase-8 and caspase-3–like activity. Furthermore, arsenic treatment down-regulated NF-κB target genes, including tumor necrosis factor-αreceptor–associated factor 1 (TRAF1), c-IAP2, interleukin-13 (IL-13), and CCR7. In contrast, cell lines with mutated, functionally inactive IκB proteins or with a weak constitutive IKK/NF-κB activity showed no alteration of the NF-κB activity and were resistant to arsenic-induced apoptosis. A direct role of the NF-κB pathway in arsenic-induced apoptosis is shown by transient overexpression of NF-κB–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-κB inhibition. We conclude that inhibition of NF-κB contributes to arsenic-induced apoptosis. Furthermore, pharmacologic inhibition of the IKK/NF-κB activity might be a powerful treatment option for Hodgkin lymphoma.