Potassium antimonyl tartrate induces caspase- and reactive oxygen species-dependent apoptosis in lymphoid tumoral cells.
The metalloid salt potassium antimonyl tartrate (PAT), previously used as an antiparasitic agent, has recently been shown to exert cytotoxicity towards acute promyelocytic leukaemia cells like arsenical compounds. In this study, we have investigated its effects towards human lymphoid malignant cells and compared them with those of arsenic trioxide (As2O3). Like As2O3, PAT was found to inhibit cell growth of various lymphoid cell lines, deriving from either acute lymphoid leukaemias (Jurkat, Molt-4 and Nalm-6) or lymphomas (Daudi, Raji and Rec1). PAT toxicity was linked, at least in part, to induction of apoptosis in both Daudi and Jurkat cells, which was dependent on caspase activity. This apoptotic process was also associated, similarly to that triggered by As2O3, with loss of mitochondrial potential and enhanced cellular production of reactive oxygen-related species. It was enhanced by co-treatment with the pro-oxidant buthionine sulphoximine and abolished in response to the antioxidant N-acetylcysteine, thus underlining that PAT toxicity, similarly to that of As2O3, is probably modulated by the redox status of the cells. PAT, used at concentrations in the micromolar range that are thought to be clinically achievable, was also demonstrated to markedly decrease the viability of primary cultured tumoral B cells that originated from 18 patients suffering from chronic lymphoid leukaemia whereas normal lymphocytes were less sensitive. These data therefore suggest that PAT may deserve to be evaluated in the treatment of some lymphoid malignancies.
Lecureur
Valérie
V
INSERM U456, Faculté de Pharmacie, Rennes, France.
Le Thiec
Aurélien
A
Le Meur
Alexandre
A
Amiot
Laurence
L
Drenou
Bernard
B
Bernard
Marc
M
Lamy
Thierry
T
Fauchet
Renée
R
Fardel
Olivier
O
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000966:Antimony Potassium Tartrate / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use; D015153:Blotting, Western; D020169:Caspases / Q000502:physiology*; D002470:Cell Survival; D003374:Coumarins / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010087:Oxides / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D001152:Arsenicals; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D005456:Fluorescent Dyes; D009842:Oligopeptides; D010087:Oxides; D017382:Reactive Oxygen Species; C102580:acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000966:Antimony Potassium Tartrate; D020169:Caspases; D000077237:Arsenic Trioxide