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Annals of Oncology Advance Access originally published online on March 17, 2008
Annals of Oncology 2008 19(8):1488-1494; doi:10.1093/annonc/mdn056
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

hematologic malignancies

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

A. Tun-Kyi1,4, J. -Z. Qin2, P. A. Oberholzer1, A. A. Navarini3, J. C. Hassel1, R. Dummer1 and U. Döbbeling1,*

1 Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
2 Skin Disease Research Laboratories, Oncology Institute, Loyola University Medical Center, Maywood, IL, USA
3 Institute for Experimental Immunology, University Hospital Zurich, Zurich, Switzerland
4 Harvard Medical School, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, USA

* Correspondence to: Dr U. Döbbeling, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland. Tel: +41 44 255 2043; Fax: + 41 44 255 2043; E-mail: udo.doebbeling{at}usz.ch

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 As2O3 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 As2O3 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 As2O3 into MF tumor-bearing mice resulted in tumor regression.

Key words: cancer therapy, cell death/survival genes, cutaneous T-cell lymphoma, gene regulation, oncogenes, transcription factors

Received for publication November 8, 2007. Revision received January 15, 2008. Accepted for publication February 7, 2008.


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