Multidrug resistance-associated protein-mediated multidrug resistance modulated by cyclosporin A in a human bladder cancer cell line

Wun Jae Kim, Yoshiyuki Kakehi, Midori Hirai, Shinji Arao, Hiroshi Hiai, Manabu Fukumoto, Osamu Yoshida

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

A doxorubicin-resistant subline (5637/DR5.5) from human bladder cancer cells (5637) was induced by stepwise increase in the doxorubicin concentration. 5637/DR5.5 cells were cross-resistant to vinblastine and etoposide but not to mitomycin C and cisplatin. We analyzed the mdr1, MRP (multidrug resistance-associated protein), and DNA topoisomerase II gene expression using the reverse transcription polymerase chain reaction assay (RT-PCR) and investigated possible differences in the accumulation and efflux of radiolabeled daunorubicin. 5637/DR5.5 cells do not express the mdr1 gene, but the expression levels of MRP are markedly higher than in drug-sensitive 5637 cells. The intracellular accumulation of radiolabeled daunorubicin was markedly decreased in the 5637/ DR5.5 cells in comparison with the parent cells. This reduced drug accumulation was associated with an enhanced drug efflux, but was reversed when cells were incubated with cyclosporin A. Cyclosporin A at the concentration of 5 μM caused 3.4-fold enhancement of daunorubicin-sensitivity in the 56377 DR5.5 cells. On the other hand, there was no difference in DNA-topoisomerase II activity between the parent and resistant cells. The resistance of the 5637/DR5.5 cells is therefore associated with an enhanced drug efflux mediated by the MRP gene overexpression, as distinct from P-glycoprotein, and is modulated by cyclosporin A.

Original languageEnglish
Pages (from-to)969-977
Number of pages9
JournalJapanese Journal of Cancer Research
Volume86
Issue number10
DOIs
Publication statusPublished - 1995 Oct 1

Keywords

  • Bladder cancer
  • Cyclosporin A
  • Doxorubicin
  • Efflux
  • Multidrug resistance
  • associated protein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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