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.
Highlights
We evaluated the effect of S-1452 and AA-2414 on the sensitivity of non-small-cell lung cancer cell lines to CDDP and carboplatin (CBDCA)
There was no significant difference in the sensitivities of PC-9 and PC-9/ CDDP cells to S-1452 or AA-2414
The sensitivities to CDDP and CBDCA of PC-9 and PC-9/CDDP cells were evaluated by MTT assay
Summary
RPMI-1640 and calcium-free and magnesium-free Dulbecco's phosphate-buffered saline (PBS) were purchased from Nissui Pharmaceutical, Tokyo, Japan. Calcium 5(Z)-1R, 2S, 3S, 4S-7-[3-phenylsulphonylaminobicyclo [2.2.1] hept-2-yl]-5-heptonoate hydrate (S-1452) (Figure 1) was obtained from the Shionogi, Osaka, Japan and (±)-7(3,5,6,-trimethyl-1, 4-benzoquinon - 2 - yl) - 7 - phenylhaptanoic acid (AA-2414) (Figure 1) was obtained from Takeda Chemical Industries, Tokyo, Japan. These antagonists were dissolved in dimethylsulphoxide (DMSO) before use. All other drugs and chemicals were purchased from Sigma Chemical Co (St Louis, MO, USA)
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