Antileukemic action of buthionine sulfoximine: evidence for an intrinsic death mechanism based on oxidative stress.
The glutathione-depleting agent buthionine sulfoximine (BSO) was found to be toxic to some AML blast populations. This toxicity was manifested as the appearance of high levels of reactive oxygen generation in GSH-depleted cells, and later by the loss of mitochondrial membrane potential and an increase in intracellular calcium. Striking heterogeneity in BSO sensitivity was observed in a series of four human AML cell lines, and in fresh leukemic blasts obtained from eight AML patients. In some cases, toxicity was seen at BSO concentrations as low as 1 microM; approximately 100-fold less than the plasma levels achieved in patients treated with BSO as a drug resistance reversing agent. Based on these results we propose that some AML blast populations are unusually dependent on GSH-based antioxidant mechanisms, due to high intrinsic rates of reactive oxygen generation. The mitochondrial respiratory chain is the most likely source of this reactive oxygen. Because toxicity is seen at clinically achievable concentrations of BSO, this agent might have antileukemic activity in patients.
Hedley
D W
DW
Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute/Princess Margaret Hospital, Canada.
McCulloch
E A
EA
Minden
M D
MD
Chow
S
S
Curtis
J
J
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D001752:Blast Crisis / Q000473:pathology*; D019328:Buthionine Sulfoximine / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000964:Antimetabolites, Antineoplastic; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D005978:Glutathione