Role of thromboxane receptor on the intracellular accumulation of cis-diamminedichloroplatinum(II) in non-small-cell but not in small-cell lung cancer cell lines.

cis-Diamminedichloroplatinum(II) (CDDP) is a key anticancer agent. It has been reported that intracellular accumulation of CDDP is an important step as a determinant for resistance to CDDP, which may be modulated by Na+, K(+)-ATPase activity. In this study, the significance of membrane Na+, K(+)-ATPase activity and the role of thromboxane (TX) receptors were evaluated using human lung cancer cell lines. In the non-small-cell lung cancer (NSCLC) cell line, EBC-1, sensitivity to CDDP was improved by treatment with two different selective thromboxane receptor antagonists, calcium 5(z)-[1R,2S,3S,4S-7-[3-phenylsulfonylaminobicyclo [2.2.1]hept-2-yl]-5-heptenoate hydrate (S-1452), and (3R)-3-(4-fluorophenyl sulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid (BAYu3405). Na+, K(+)-ATPase was activated and intracellular accumulation of CDDP increased with treatment in EBC-1. In the small-cell lung cancer (SCLC) cell lines, SBC-1, sensitivity to CDDP and Na+, K(+)-ATPase activity did not change significantly, and intracellular accumulation of CDDP was not modulated. These results suggest the importance of the TX receptors as determinants of the sensitivity to CDDP in NSCLC cell lines. However, Na+, K(+)-ATPase activity and the role of TX receptors may not be so significant in the resistance mechanisms to CDDP in SCLC cell lines. In EBC-1 cells, the specific binding of S-145 was evident, but not in SBC-1 cells. The difference in TX receptors in NSCLC and SCLC cell lines may be one of the reasons for the variety of the antitumor effects of CDDP in chemotherapy for lung cancer.