Anthracycline resistance in murine leukemic P388 cells. Role of drug efflux and glutathione related enzymes.

Abstract:

:Energy-dependent drug efflux is a major factor in cellular resistance of P388/R84 mouse leukemic cells to anthracyclines such as doxorubicin (DOX), and blocking of efflux increases sensitivity. However, efflux does not play a significant role in resistance to N-trifluoroacetyladriamycin-14-valerate (AD 32), a DOX analog. Since drug efflux alone cannot account for resistance to anthracyclines, we have, in the present study, measured cellular glutathione (GSH) content and activity of GSH cycle related enzymes to determine their role in resistance. Cellular GSH content was similar in DOX-sensitive and -resistant mouse leukemic cells (P388 and P388/R84). GSH peroxidase, glucose-6-phosphate dehydrogenase and glutathione reductase activities were 1.36-, 1.58- and 1.14-fold higher in P388/R84 cells. Incubation of P388/R84 cells with 100 microM buthionine-S,R-sulfoximine (BSO) for 24 hr reduced cellular GSH content to 6% of control and reduced their resistance to DOX [dose modification factor (DMF) 3.9]. GSH depletion had no significant effect on the cytotoxicity of AD 32 (DMF 1.5). Exposure of P388/R84 cells to BSO (for GSH depletion) and trifluoperazine (for efflux blocking) further reduced their resistance to DOX (DMF 14). These results indicate that DOX resistance in P388/R84 cells is multifactorial and that changes in GSH cycle related enzymes such as GSH peroxidase may also contribute to their resistance.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Nair S,Singh SV,Samy TS,Krishan A

doi

10.1016/0006-2952(90)90151-a

subject

Has Abstract

pub_date

1990-02-15 00:00:00

pages

723-8

issue

4

eissn

0006-2952

issn

1873-2968

pii

0006-2952(90)90151-A

journal_volume

39

pub_type

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