Mechanism of cross‐resistance to cisplatin in a mitomycin C‐resistant human bladder cancer cell line

Published May 4, 1995International journal of cancer

How resistance to mitomycin C may cause resistance to cisplatin in human bladder cancer cells

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Abstract

The J82/MMC cell line displayed 2- to 3-fold cross-resistance to cisplatin compared to parental J82/WT cells.

Cross-resistance to cisplatin in J82/MMC cells is independent of reduced platinum accumulation.
J82/MMC cells show approximately a 1.5-fold resistance to cadmium chloride, indicating increased metallothionein content.
Northern blot analysis revealed a 2.7-fold increase in MT-IIA mRNA levels in J82/MMC cells compared to J82/WT.
Elevated glutathione transferase activity in J82/MMC cells is linked to over-expression of pi-type GST protein.
GSH depletion enhances cisplatin cytotoxicity more significantly in J82/MMC cells (about 2.1-fold) compared to J82/WT (about 1.6-fold).

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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.

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Mechanism of cross‐resistance to cisplatin in a mitomycin C‐resistant human bladder cancer cell line

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