Ouabain-resistant non-small-cell lung-cancer CELL LINE SHOWS COLLATERAL SENSITIVITY TO cis-diamminedichloroplatinum(II) (CDDP)

Authors

  • Tohru Ohmori,

    1. Pharmacology Division of National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan
    2. First Department of Internal Medicine, Showa University, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142, Japan
    Search for more papers by this author
  • Kazuto Nishio,

    1. Pharmacology Division of National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan
    Search for more papers by this author
  • Sei Ohta,

    1. Pharmacology Division of National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan
    Search for more papers by this author
  • Naohiro Kubota,

    1. Pharmacology Division of National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan
    Search for more papers by this author
  • Mitsuru Adachi,

    1. First Department of Internal Medicine, Showa University, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142, Japan
    Search for more papers by this author
  • Kazuhide Komiya,

    1. Department of Radiopharmacy, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142, Japan
    Search for more papers by this author
  • Nagahiro Saijo

    Corresponding author
    1. Pharmacology Division of National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan
    • Pharmacology Division of National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan
    Search for more papers by this author

Abstract

We have reported that the cellular uptake of cis-diamminedi-chloroplatinum(11) (CDDP) was inhibited by an Na+,K+-adenosine triphosphatase (ATPase) inhibitor, ouabain, in a human non-small-cell lung-cancer cell line, PC-14, but not in its CDDP-resistant cell line, PC-14/CDDP. [3H]Ouabain binding of PC-14/CDDP was about 50% lower than that of PC-14. Accordingly, we speculated that a decrease in Na+,K+-ATPase activity in PC-14/CDDP might contribute to the decrease in cellular CDDP accumulation. To clarify the relationship between the activity or expression of Na+,K+-ATPase and cellular CDDP accumulation, we established an ouabain-resistant non-small-cell lung-cancer cell line (PC-14/OB300), which showed 1.9-fold resistance to the cytotoxicity of ouabain. Interestingly, this cell line was 4.2-fold more sensitive to CDDP than PC-14. The accumulation of CDDP in PC-14/OB300 was increased to 2.7-fold that in PC-14. This elevation of CDDP accumulation was not considered to be caused by increased passive diffusion, because the accumulation of CDDP in PC-14/OB300 was also inhibited by ouabain compared to PC-14. As one of the indices of Na+.K+-ATPase activity, we determined cellular 86Rb+ influx rates. The 86Rb+ influx rate was 1.5-fold higher in PC-14/OB300 and fell to 0.7-fold in PC-14/CDDP compared with PC-14. The mRNA expression of Na+,K+-ATPase was increased in PC-14/OB300 and decreased in PC- 14/CDDP. There was no difference in cellular [3H]ouabain binding between PC-14/OB300 and PC-14. It is passible that Na+,K+-ATPase of PC-14/OB300 has a different affinity for ouabain from that of PC-14. Our results suggest that the enzyme activity or the level of expression of Na+,K+-ATPase may contribute to the cellular uptake of CDDP and determine the sensitivity to CDDP. © Wiley-Liss, Inc.

Ancillary