Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model

Abstract

Background: Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma (CTCL). Arsenic trioxide (As2O3) has recently been shown to be effective against leukemias, so we studied whether As2O3 induces apoptosis of CTCL cells in vitro. We further investigated if As2O3 is effective in a MF mouse model. Material and methods: Annexin V/7-amino-actinomycin-D stainings were carried out to investigate if As2O3 induced apoptosis of CTCL cell lines. To study the underlying mechanisms, the effects of As2O3 on various transcription factors and apoptosis regulating proteins were analyzed by western blots, electrophoretic mobility shift assays and transcription factor enzyme-linked immunosorbent assays. The ability of As2 O3 to induce tumor regression was investigated in a MF mouse model. Results: As2O3-induced apoptosis was paralleled by a reduction of the DNA-binding activities of transcription factors of the NFkB and signal transducer and activator of transcription gene families and reduced expression of the antiapoptotic proteins bcl-1, bcl-xL and mcl-1. Local injections of 200 μM As2 O3 into tumors caused complete remissions in five of six mice and one partial remission. Conclusions: As2O3 induced apoptosis of CTCL cells by the down-regulation of transcription factors that stimulate the expression of antiapoptotic genes. Local injection of As2 O3 into MF tumor-bearing mice resulted in tumor regression. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.