The mechanism of the difference in cellular uptake of platinum derivatives in non-small cell lung cancer cell line (PC-14) and its cisplatin-resistant subline (PC-14/CDDP).
A cisplatin-resistant non-small cell lung cancer cell line, PC-14/CDDP, was established from PC-14 by stepwise escalation of CDDP concentrations in vitro. PC-14/CDDP cells were 11.4-fold more resistant to CDDP compared with PC-14 cells. This resistant cell line was cross-resistant to platinum analogues, such as carboplatin (CBDCA) (x 3.5), cis-diammine(glycolate-O,O')platinum(II) (254-S) (x 5.6) and cis-dichloro(ethylenediammine)platinum(II) (cis-DEP) (x 4.2). On the other hand, relative resistance value to ormaplatin was only 1.4-fold. To elucidate the mechanism(s) of CDDP resistance and of its circumvention by ormaplatin, we investigated the characteristics of this cell line. Total sulfhydryl content was slightly elevated in PC-14/CDDP cells compared with PC-14 cells. There was no significant difference in the DNA repair ability between the two cell lines. Cellular accumulations of CDDP, CBDCA, 254-S, and cis-DEP in PC-14/CDDP cells were markedly decreased to 23%, 27%, 29%, and 32% of those in PC-14 cells, respectively. However, the accumulation of ormaplatin in PC-14/CDDP was almost the same as that in PC-14. To elucidate the mechanisms of uptake of these platinum analogs in the cells, we studied the effects of ouabain, an Na+,K(+)-ATPase inhibitor, on cellular drug uptake in both cell lines. Preincubation with 300 nM ouabain for 1 h inhibited approximately 60% of CDDP accumulation in PC-14. However ouabain preincubation at any concentration up to 300 nM did not affect CDDP accumulation in PC-14/CDDP. The accumulation of ormaplatin was not inhibited by ouabain in either of the cell lines. These data suggest that the mechanism of the uptake of ormaplatin is different from that of CDDP, and that ormaplatin exerts a cytotoxic effect in CDDP-resistant cells which have defective cisplatin accumulation.
Pharmacology Division, National Cancer Center Hospital, Tokyo.
T
T
Ohmori
T
T
Morikage
Y
Y
Sugimoto
Y
Y
Fujiwara
K
K
Kasahara
K
K
Nishio
S
S
Ohta
Y
Y
Sasaki
T
T
Takahashi
N
N
Saijo
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D002999:Clone Cells; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000494:pharmacology*; D010042:Ouabain / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D013438:Sulfhydryl Compounds; D010042:Ouabain; D002945:Cisplatin