Modulation of sensitivity to cis-diamminedichloroplatinum (II) by thromboxane A₂ receptor antagonists in non-small-cell lung cancer cell lines

Abstract

We examined the effect of selective thromboxane A2 (TXA2) receptor antagonists, calcium 5(Z)-1R, 2S, 3S, 4S-7-[3-phenylsulphonylaminobicyclo [2.2.1] hept-2-yl]-5-heptonoate hydrate (S-1452) and +/- -7-(3,5,6,-trimethyl-1,4-benzoquinon-2-yl)-7-phenylhaptanoic acid (AA-2414), on sensitivity to cis-diamminedichloroplatinum (II) (CDDP) in non-small-cell lung cancer cell lines. IC50 values to CDDP using MTT assay were decreased 2.1- and 4.6-fold respectively by treatment with 250 or 500 microM S-1452, for a 2 h simultaneous drug exposure, and those of PC-9/CDDP, a CDDP-resistant cell line, were decreased 3.1- and 6.1-fold. Sensitivity to carboplatin was also enhanced by the treatment with S-1452. IC50 values to CDDP and carboplatin were decreased by treatment with AA-2414 in a dose-dependent manner. Isobologram analysis showed that the combination of CDDP with S-1452 or AA-2414 produced supra-additive or additive effects in each cell line. Neither glutathione content nor glutathione S-transferase activity was changed in either cell line by treatment with 500 microM S-1452. Accumulation of platinum into PC-9 and PC-9/CDDP was increased by the treatment in a dose-dependent manner. Na+, K+-ATPase activity of PC-9 and PC-9/CDDP was enhanced by the treatment of S-1452 in a dose-dependent manner. These data show that the TXA2 receptor antagonists may enhance the sensitivity of non-small-cell lung cancer cell lines to platinum agents. Increase in Na+, K+-ATPase activity induced by S-1452 may be the mechanism of its sensitising effect through increase in platinum accumulation.