Differential toxicity of antimonial compounds and their effects on glutathione homeostasis in a human leukaemia monocyte cell line.
Trivalent antimonial compounds (Sb(III)), originally used in the treatment of leishmaniasis, are now being proposed as a novel therapy for acute promyelocytic leukaemia (APL). Here, we examine the effects of Sb(III) and pentavalent antimonial drugs (Sb(V)) on glutathione homeostasis, oxidative stress and apoptosis in the human leukaemia monocyte cell line, THP-1. Although growth of THP-1 macrophages is unaffected by Sb(V), macrophages are extremely sensitive to Sb(III). On exposure to Sb(III), intracellular free glutathione (GSH) levels in macrophages decrease linearly by 50% over 4h, associated with efflux of both GSH and accumulation of intracellular glutathione disulphide (GSSG). Together these effects increase the redox potential of the GSSG/GSH couple from -282 to -225mV. Sb(III)-induced GSH efflux from THP-1 macrophages is accompanied by the concomitant efflux of Sb(III) at a constant molar ratio of 3 (GSH) to 1 (Sb(III)), respectively. Sb(III) directly inhibits glutathione reductase activity in macrophages, significantly retarding the regeneration of GSH from GSSG, following diamide oxidation. Sb(III)-treated THP-1 macrophages go on to exhibit elevated levels of reactive oxygen species and show the early signs of apoptosis. The absence of these effects in Sb(V)-treated THP-1 cells suggests that macrophages do not efficiently reduce Sb(V) to Sb(III). Collectively, these findings suggest that Sb(III) seriously compromises thiol homeostasis in THP-1 macrophages and that this may be an early defining event in the mode of action of antimonials against leukaemia cells.
Wyllie
Susan
S
Division of Biological Chemistry and Molecular Biology, Wellcome Trust Biocentre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH Scotland, UK.
Fairlamb
Alan H
AH
D000966:Antimony Potassium Tartrate / Q000494:pharmacology*; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D007938:Leukemia; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D000966:Antimony Potassium Tartrate; D005980:Glutathione Reductase; D005978:Glutathione; D000967:Antimony Sodium Gluconate