TY - JOUR
T1 - Differential toxicity of antimonial compounds and their effects on glutathione homeostasis in a human leukaemia monocyte cell line
AU - Wyllie, Susan
AU - Fairlamb, Alan H.
N1 - Funding Information:
This work was funded by a grant from the Burroughs Wellcome Fund and Wellcome Trust Infectious Disease Initiative. We thank Dr. Cornelia Oetke for assistance with FACS analysis, Neil Greig for help with preliminary studies and Dr. Terry Smith for useful comments and suggestions.
PY - 2006/1/12
Y1 - 2006/1/12
N2 - Trivalent antimonial compounds (SbIII), 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 SbIII and pentavalent antimonial drugs (SbV) 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 SbV, macrophages are extremely sensitive to SbIII. On exposure to Sb III, intracellular free glutathione (GSH) levels in macrophages decrease linearly by 50% over 4 h, 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 -225 mV. SbIII-induced GSH efflux from THP-1 macrophages is accompanied by the concomitant efflux of SbIII at a constant molar ratio of 3 (GSH) to 1 (SbIII), respectively. SbIII 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 SbV-treated THP-1 cells suggests that macrophages do not efficiently reduce SbV to SbIII. Collectively, these findings suggest that SbIII 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.
AB - Trivalent antimonial compounds (SbIII), 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 SbIII and pentavalent antimonial drugs (SbV) 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 SbV, macrophages are extremely sensitive to SbIII. On exposure to Sb III, intracellular free glutathione (GSH) levels in macrophages decrease linearly by 50% over 4 h, 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 -225 mV. SbIII-induced GSH efflux from THP-1 macrophages is accompanied by the concomitant efflux of SbIII at a constant molar ratio of 3 (GSH) to 1 (SbIII), respectively. SbIII 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 SbV-treated THP-1 cells suggests that macrophages do not efficiently reduce SbV to SbIII. Collectively, these findings suggest that SbIII 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.
KW - Antimonials
KW - Apoptosis
KW - Glutathione
KW - Leukaemia
KW - Macrophage
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=29144473741&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2005.10.043
DO - 10.1016/j.bcp.2005.10.043
M3 - Article
C2 - 16318845
AN - SCOPUS:29144473741
SN - 0006-2952
VL - 71
SP - 257
EP - 267
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 3
ER -