Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model.
BACKGROUND
Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma (CTCL). Arsenic trioxide (As(2)O(3)) has recently been shown to be effective against leukemias, so we studied whether As(2)O(3) induces apoptosis of CTCL cells in vitro. We further investigated if As(2)O(3) is effective in a MF mouse model.


METHODS
Annexin V/7-amino-actinomycin-D stainings were carried out to investigate if As(2)O(3) induced apoptosis of CTCL cell lines. To study the underlying mechanisms, the effects of As(2)O(3) 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 As(2)O(3) to induce tumor regression was investigated in a MF mouse model.


RESULTS
As(2)O(3)-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 muM As(2)O(3) into tumors caused complete remissions in five of six mice and one partial remission.


CONCLUSIONS
As(2)O(3) induced apoptosis of CTCL cells by the down-regulation of transcription factors that stimulate the expression of antiapoptotic genes. Local injection of As(2)O(3) into MF tumor-bearing mice resulted in tumor regression.
Tun-Kyi
A
A
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Harvard Medical School, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, USA.
Qin
J-Z
JZ
Skin Disease Research Laboratories, Oncology Institute, Loyola University Medical Center, Maywood, IL, USA.
Oberholzer
P A
PA
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Navarini
A A
AA
Institute for Experimental Immunology, University Hospital Zurich, Zurich, Switzerland.
Hassel
J C
JC
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Dummer
R
R
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Döbbeling
U
U
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. Electronic address: udo.doebbeling@usz.ch.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009182:Mycosis Fungoides / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D001152:Arsenicals; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000077237:Arsenic Trioxide