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

摘要

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.