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)

Tohru Ohmori, Toshihiko Morikage, Yoshikazu Sugimoto, Yasuhiro Fujiwara, Kazuo Kasahara, Kazuto Nishio, Sei Ohta, Yasutsuna Sasaki, Terumi Takahashi, Nagahiro Saijo

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Abstract

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) (×3.5), cis-diammine(glycolate-O,O′)platinum(II) (254-S) (×5.6) and cis-dichloro(ethylenediammine)platinum(II) (cis-DEP) (×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.

Original languageEnglish
Pages (from-to)83-92
Number of pages10
JournalJapanese Journal of Cancer Research
Volume84
Issue number1
Publication statusPublished - 1993 Jan
Externally publishedYes

Fingerprint

ormaplatin
Platinum
Non-Small Cell Lung Carcinoma
Cisplatin
Cell Line
Ouabain
Carboplatin
glycolic acid
DNA Repair

Keywords

  • Cisplatin resistance
  • Drug accumulation
  • Lung cancer
  • Ormaplatin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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). / Ohmori, Tohru; Morikage, Toshihiko; Sugimoto, Yoshikazu; Fujiwara, Yasuhiro; Kasahara, Kazuo; Nishio, Kazuto; Ohta, Sei; Sasaki, Yasutsuna; Takahashi, Terumi; Saijo, Nagahiro.

In: Japanese Journal of Cancer Research, Vol. 84, No. 1, 01.1993, p. 83-92.

Research output: Contribution to journalArticle

Ohmori, Tohru ; Morikage, Toshihiko ; Sugimoto, Yoshikazu ; Fujiwara, Yasuhiro ; Kasahara, Kazuo ; Nishio, Kazuto ; Ohta, Sei ; Sasaki, Yasutsuna ; Takahashi, Terumi ; Saijo, Nagahiro. / 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). In: Japanese Journal of Cancer Research. 1993 ; Vol. 84, No. 1. pp. 83-92.
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abstract = "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) (×3.5), cis-diammine(glycolate-O,O′)platinum(II) (254-S) (×5.6) and cis-dichloro(ethylenediammine)platinum(II) (cis-DEP) (×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.",
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AU - Morikage, Toshihiko

AU - Sugimoto, Yoshikazu

AU - Fujiwara, Yasuhiro

AU - Kasahara, Kazuo

AU - Nishio, Kazuto

AU - Ohta, Sei

AU - Sasaki, Yasutsuna

AU - Takahashi, Terumi

AU - Saijo, Nagahiro

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N2 - 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) (×3.5), cis-diammine(glycolate-O,O′)platinum(II) (254-S) (×5.6) and cis-dichloro(ethylenediammine)platinum(II) (cis-DEP) (×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.

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