UP-REGULATION OF GAMMA-GLUTAMYLCYSTEINE SYNTHETASE-ACTIVITY IN MELPHALAN-RESISTANT HUMAN MULTIPLE-MYELOMA CELLS EXPRESSING INCREASED GLUTATHIONE LEVELS

被引:66
作者
MULCAHY, RT
BAILEY, HH
GIPP, JJ
机构
关键词
GLUTATHIONE; MELPHALAN; GAMMA-GLUTAMYLCYSTEINE SYNTHETASE;
D O I
10.1007/s002800050105
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Levels of intracellular glutathione (GSH) and the GSH-related enzymes gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyltranspeptidase (gamma-GT) were measured in the melphalan-resistant human multiple myeloma cell line 8226/LR-5 and were compared to those measured in the drug-sensitive 8226/S and doxorubicin-resistant 8226/Dox40 cell lines. Both GSH and gamma-GCS activity, the rate-limiting step in the de novo synthesis of GSH, were elevated by a factor of approximately 2 in the melphalan-resistant 8226/LR-5 cells relative to the other two lines. gamma-GT activity was not elevated significantly in the /LR-5 cells. Northern analysis with a probe specific for the large subunit of human liver gamma-GCS identified two bands (3.2 and 4.0 kb), both of which were increased by a factor of 2-3 in the 8226/LR-5 line. Levels of gamma-GCS mRNA expression were comparable in the /S and /Dox40 cell lines. Levels of gamma-GT mRNA were similar in the /S and /LR-5 lines but were reduced in the /Dox40 cells. These data suggest that the increased GSH levels associated with resistance to melphalan in the 8226/LR-5 myeloma cells is attributable to up-regulation of gamma-GCS. This observation is consistent with recent demonstrations of up-regulation of gamma-GCS in melphalan-resistant prostate carcinoma cells and cisplatinum-resistant ovarian carcinoma cells, suggesting that increased expression of gamma-GCS may be an important mediator of GSH-associated resistance mechanisms.
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页码:67 / 71
页数:5
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