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

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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.

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