title: Active efflux system for cisplatin in cisplatin-resistant human KB cells.
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 microM 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.
authors.affiliation: Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University.
authors.forename: R
authors.initials: R
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Mutoh
authors.forename: K
authors.initials: K
authors.lastname: Niwa
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Aikou
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.forename: M
authors.initials: M
authors.lastname: Kuwano
authors.forename: S
authors.initials: S
authors.lastname: Akiyama
mesh_terms: D001693:Biological Transport, Active; D002945:Cisplatin / Q000378:metabolism*; D004351:Drug Resistance; D005799:Genes, Dominant; D006801:Humans; D014407:Tumor Cells, Cultured
chemical_list: D002945:Cisplatin