Document Detail

Arsenic trioxide induces apoptosis of cutaneous T cell lymphoma cells: evidence for a partially caspase-independent pathway and potentiation by ascorbic acid (vitamin C).
MedLine Citation:
PMID:  14632209     Owner:  NLM     Status:  MEDLINE    
Arsenic trioxide (As2O3) displays apoptogenic properties against various types of hematopoietic malignancies. We investigated the effects of As2O3 on the viability of the cutaneous T cell lymphoma cell lines HuT-78, SeAx, and Myla, and of peripheral blood mononuclear cells from patients with Sézary syndrome, by using propidium iodide and annexin-V staining, terminal deoxyuridine triphosphate nick end labeling (TUNEL), cell cycle analysis, mitochondrial transmembrane potential (delta psi(m)) alterations, cytochrome c release, and detection of processed caspase-3. We also report in vivo effects of As2O3 in two patients with cutaneous T cell lymphoma. The results show that As2O3 induces apoptosis of cutaneous T cell lymphoma lines and of Sézary cells from patients in a time- and concentration-dependent manner in vitro, as demonstrated by annexin-V staining, mitochondrial depolarization, and DNA fragmentation. Ascorbic acid 100 microM potentiated As2O3-induced Sézary cell death, whereas interferon-alpha had no synergistic effect. As2O3-induced Sézary cell death involves activation of caspase-3, cleavage of poly(ADP-ribose)polymerase, and cytochrome c release, but was only partially inhibited by the pancaspase inhibitor Z-VAD.fluoromethylketone. Finally, As2O3 was administered to two patients with cutaneous T cell lymphoma, allowing us to obtain a partial response in one case, whereas stability was observed in the second patient. These results demonstrate that As2O3 synergizes with ascorbic acid to induce Sézary cell death at clinically achievable concentrations, through a caspase-partially independent pathway, and provide a rationale for further in vivo studies addressing the therapeutic efficacy of As2O3 in cutaneous T cell lymphoma patients.
Laurence Michel; Alain Dupuy; Francette Jean-Louis; Aurore Sors; Joël Poupon; Manuelle Viguier; Philippe Musette; Louis Dubertret; Laurent Degos; Hervé Dombret; Hervé Bachelez
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of investigative dermatology     Volume:  121     ISSN:  0022-202X     ISO Abbreviation:  J. Invest. Dermatol.     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-11-24     Completed Date:  2003-12-12     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0426720     Medline TA:  J Invest Dermatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  881-93     Citation Subset:  IM    
Skin Research Institute, Institut National de la Santé et de la Recherche Médicale U532, Department of Dermatology, Hôpital Saint-Louis, Paris, France.
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MeSH Terms
Antineoplastic Agents / administration & dosage*,  pharmacology
Antioxidants / pharmacology*
Apoptosis / drug effects*,  physiology
Arsenicals / administration & dosage*,  pharmacology
Ascorbic Acid / pharmacology*
Caspases / metabolism
Cell Division / drug effects
Cell Line, Tumor
Clone Cells
Drug Synergism
Leukocytes, Mononuclear / cytology,  drug effects
Lymphoma, T-Cell, Cutaneous / drug therapy*
Middle Aged
Mitochondria / drug effects
Oxides / administration & dosage*,  pharmacology
Skin Neoplasms / drug therapy*
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antioxidants; 0/Arsenicals; 0/Oxides; 1327-53-3/arsenic trioxide; 50-81-7/Ascorbic Acid; EC 3.4.22.-/Caspases

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