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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 May;93(5):582–590. doi: 10.1111/j.1349-7006.2002.tb01294.x

Dexamethasone‐resistant Human Pre‐B Leukemia 697 Cell Line Evolving Elevation of Intracellular Glutathione Level: An Additional Resistance Mechanism

Hitoshi Inoue 1, Haruyuki Takemura 1, Yasukazu Kawai 1, Akira Yoshida 1, Takanori Ueda 1,✉, Toshiyuki Miyashita 2
PMCID: PMC5927028  PMID: 12036455

Abstract

Glucocorticoids remain among the most important drugs in the treatment of acute lymphoblastic leukemia (ALL). Although the mechanisms of glucocorticoid resistance have been studied in some T‐cell leukemic cell lines, less work has been done with B‐cell lines. We established a dexamethasone (DEX)‐resistant human pre‐B lineage leukemia cell line (697/DEX) and investigated the mechanism of resistance. 697/DEX was over 430–fold more resistant to DEX compared with the parental cells (697/Neo). Overexpression of Bcl–2 protein was not observed in 697/DEX, different from the mechanism of resistance in Bcl–2–virus‐infected cells (697/Bcl–2). Although the expression of p‐glycoprotein (Pgp) in 697/DEX was positive, its functional activity was not detected. The numbers of glucocorticoid receptors (GR) in 697/DEX and 697/Bcl–2 were significantly lower than those in 697/Neo. In addition, 697/DEX and 697/Bcl–2 had higher levels of glutathione (GSH) than 697/Neo. In the presence of l‐buthionine‐(S, R)‐sulfoximine (BSO), an inhibitor of GSH synthesis, both 697/DEX and 697/Bcl–2 recovered their sensitivity to DEX. Interestingly, cell death by the depletion of GSH did not involve caspase–3/7 activation in 697/Bcl–2 and 697/DEX, different from 697/Neo, suggesting a death mechanism through caspase‐independent programmed cell death or necrosis. In conclusion, DEX‐resistance in 697/DEX was related not only to a GR decrease, but also to an increase in intracellular GSH level in the DEX‐resistant B‐cell leukemia cell line. Circumvention of DEX‐resistance with BSO may offer an approach to overcoming resistance to chemotherapy in B‐cell lineage ALL.

Keywords: Dexamethasone (DEX), 697 cells, Bcl–2, Glutathione (GSH), Caspase–3

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