Mechanism of cross-resistance to cisplatin in a mitomycin C-resistant human bladder cancer cell line.
This study was undertaken to elucidate the mechanism(s) of cross-resistance to cisplatin (CDDP) in a mitomycin C (MMC)-resistant human bladder cancer cell line, J82/MMC. The J82/MMC cell line displayed 2- to 3-fold cross-resistance to CDDP and carboplatin when compared to the parental J82/WT cells. Drug uptake studies revealed that cross-resistance to CDDP in the J82/MMC cell line was independent of reduced platinum accumulation. The J82/MMC cell line exhibited approximately a 1.5-fold resistance to cadmium chloride, an indicator for increased metallothionein (MT) content, when compared to the J82/WT cells. Northern blot analysis showed a 2.7-fold higher level of MT-IIA mRNA in the J82/MMC cell line compared with J82/WT. We have reported previously that, whereas glutathione (GSH) level is comparable in these cells, GSH transferase (GST) activity is significantly higher in the J82/MMC cell line compared with J82/WT. Results of the present study showed that the elevated GST activity in the J82/MMC cell line was due to an over-expression of pi-type GST protein. Although buthionine-S,R-sulfoximine (BSO)-induced GSH depletion significantly enhanced CDDP cytotoxicity in both cell lines, the magnitude of potentiation was markedly higher in J82/MMC cells (about 2.1-fold) relative to J82/WT (about 1.6-fold). Our results suggest that cross-resistance to CDDP in the J82/MMC cell line may be due to alterations in cellular thiols.
Singh
S V
SV
Mercy Cancer Institute, Mercy Hospital, Pittsburgh, PA, USA.
Xu
B H
BH
Jani
J P
JP
Emerson
E O
EO
Backes
M G
MG
Rihn
C
C
Scalamogna
D
D
Stemmler
N
N
Specht
S
S
Blanock
K
K
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001692:Biological Transport; D019328:Buthionine Sulfoximine; D002104:Cadmium / Q000633:toxicity; D019256:Cadmium Chloride; D016190:Carboplatin / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002712:Chlorides / Q000633:toxicity; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D004351:Drug Resistance; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D007700:Kinetics; D008668:Metallothionein / Q000096:biosynthesis; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D016685:Mitomycin / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms
D000964:Antimetabolites, Antineoplastic; D002712:Chlorides; D007527:Isoenzymes; D012333:RNA, Messenger; D002104:Cadmium; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D016685:Mitomycin; D008668:Metallothionein; D016190:Carboplatin; D005982:Glutathione Transferase; D005978:Glutathione; D019256:Cadmium Chloride; D002945:Cisplatin