Identification of multidrug resistance-associated protein 1 and glutathione as multidrug resistance mechanisms in human prostate cancer cells: chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine.
OBJECTIVE
To assess the involvement of the multidrug resistance-associated protein 1 (MRP1) and the glutathione pathway in the multidrug resistant (MDR) phenotype of prostate cancer in vitro.


METHODS
Chemoselection of human prostate cancer cell lines PC3 and DU145 with etoposide resulted in the resistant cell lines PC3-R and DU-R. Resistance against etoposide, doxorubicin and vincristine, and its reversal with leukotriene D4 antagonists MK-571 and zafirlukast, and buthionine sulfoximine (BSO), was assessed using tetrazolium-dye viability assays. Western blot analysis of MRP1 expression and glutathione content were measured, and MRP1 function assessed in fluorescence assays.


RESULTS
MRP1 was increased in the MDR models; the glutathione content was significantly higher in PC3-R but there was no increase in glutathione in DU-R. Adding non-toxic doses of MK-571, zafirlukast or BSO significantly increased the sensitivity of the MDR models to cytotoxic drugs. MRP1 function was inhibited with MK-571 in the MDR models.


CONCLUSIONS
MRP1 and glutathione mediate MDR in newly developed prostate cancer models.
van Brussel
J P
JP
Institute of Urology, Erasmus Medical Center, Rotterdam, The Netherlands. brusselcontant@freeler.nl
Oomen
M A
MA
Vossebeld
P J M
PJ
Wiemer
E A C
EA
Sonneveld
P
P
Mickisch
G H J
GH
D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology
D019328:Buthionine Sulfoximine; D004791:Enzyme Inhibitors; D005978:Glutathione; D020024:Leukotriene Antagonists; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; C059141:verlukast; C421109:multidrug resistance-associated protein 1