Glutathione depletion restores the susceptibility of cisplatin-resistant chronic myelogenous leukemia cell lines to Natural Killer cell-mediated celldeath via necrosis rather than apoptosis

We investigated the effect of intracellular glutathione (GSH) levels on Nat ural Kitter-mediated apoptosis in cisplatin-resistant K562 cells. K562/B6 a nd K562/C9 are cisplatin-resistant K562 cells less susceptible to lysis by natural killer cells. Cisplatin-resistant K562 cells did not present the ap optotic pattern of DNA fragmentation as it was observed for their maternal counterparts. K562/B6 and K562/C9 cell tines produce 1.6- and 1.9-times mor e GSH than K562 cells. Treatment of both cell lines with D,L-buthionine-(S, R)-sulfoximine (BSO, a gamma -glutamyl cysteine synthetase inhibitor) decre ased 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 re duction 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 t han apoptosis.