Glutathione depletion restores the susceptibility of cisplatin-resistant chronic myelogenous leukemia cell lines to Natural Killer cell-mediated cell death via necrosis rather than apoptosis.
We investigated the effect of intracellular glutathione (GSH) levels on Natural Killer-mediated apoptosis in cisplatin-resistant K562 cells. K562/B6 and K562/C9 are cisplatin-resistant K562 cells less susceptible to lysis by natural killer cells. Cisplatin-resistant K562 cells did not present the apoptotic pattern of DNA fragmentation as it was observed for their maternal counterparts. K562/B6 and K562/C9 cell lines produce 1.6- and 1.9-times more GSH than K562 cells. Treatment of both cell lines with D,L-buthionine-(S,R)-sulfoximine (BSO, a gamma-glutamyl cysteine synthetase inhibitor) decreased GSH levels and augmented cell death induced by NK cells via a necrotic rather than an apoptotic process. Proliferating cell nuclear antigen (PCNA) expression was elevated in cisplatin-resistant K562 subclones, and the reduction of GSH levels after treatment with BSO decreased the expression of PCNA. These results suggest that the GSH level affects the NK cell-mediated cell death of cisplatin-resistant K562 cells by inducing necrosis rather than apoptosis.
Dedoussis
G V
GV
Department of Dietetics-Nutrition, Harokopio University, Kallithea, Athens, Greece. dedousi@hua.gr
Andrikopoulos
N K
NK
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002469:Cell Separation; D002945:Cisplatin / Q000494:pharmacology; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000502:physiology*; D009336:Necrosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D018809:Proliferating Cell Nuclear Antigen; D019328:Buthionine Sulfoximine; D005978:Glutathione; D002945:Cisplatin