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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1994 Apr;85(4):426–433. doi: 10.1111/j.1349-7006.1994.tb02376.x

Active Efflux System for Cisplatin in Cisplatin‐resistant Human KB Cells

Ryu‐ichi Fujii 1, Masato Mutoh 2, Kiyoshi Niwa 3, Kazutaka Yamada 3, Takashi Aikou 3, Masayuki Nakagawa 4, Michihiko Kuwano 5, Shin‐ichi Akiyama 1,✉
PMCID: PMC5919474  PMID: 8200854

Abstract

Mutants, KCP‐4 and PC‐5, resistant to an anticancer agent, cisplatin, were selected in multiple steps from human epidermoid KB carcinoma cells and human prostate PC‐3 carcinoma cells, respectively. KCP‐4 and PC‐5 were 63 and 10 fold more resistant to cisplatin than the parental cells, respectively. KCP‐4 cells exhibited increased resistance to cisplatin analogues and were also slightly cross‐resistant to melphalan, cyclophosphamide, mitomycin C and methotrexate. KCP‐4 cells were not cross‐resistant to doxorubicin, daunorubicin, vincristine or CdSO4. The accumulations of cisplatin in KCP‐4 cells and PC‐5 in medium containing 50 μM cisplatin were approximately 20% of those in the parental cells. Revertant analysis suggested that a defect in cisplatin accumulation may be related to cisplatin resistance in PC‐5 cells. The uncoupling agent of oxidative phosphorylation, 2,4‐dinitrophenol, increased the accumulation of cisplatin in KCP‐4 and cisplatin‐resistant human prostate carcinoma PC‐5 cells to nearly the same level as in their parental KB‐3‐1 and human prostate carcinoma PC‐3 cells without 2,4‐dinitrophenol, but did not increase accumulation in KB‐3‐1 and PC‐3 cells. Addition of glucose in the medium inhibited the enhancement of cisplatin accumulation in KCP‐4 cells by 2,4‐dinitrophenol. Enhanced active efflux of cisplatin from KCP‐4 cells was observed. A cell‐cell hybridization test showed that the cisplatin resistance and the accumulation defect behaved as codominant traits. These data suggest that an active efflux system for cisplatin exists in cisplatin‐resistant KCP‐4 cells.

Keywords: Cisplatin resistance, Accumulation defect, Enhanced efflux

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