Up-regulation of ICH-1L protein by thromboxane A2 antagonists enhances cisplatin-induced apoptosis in non-small-cell lung-cancer cell lines

We evaluated the effect of thromboxane A(2) (TXA(2)) blockade on cisplatin-induced apoptosis in nonsmall-cell lung cancer (NSCLC) cell lines. Cisplatin induced apoptosis in PC/9 and PC-9/CDDP in a dose-dependent manner. Treatment with specific TXA(2) antagonist, calcium 5(Z)-1R,2S,3S,4S-7-[3-phenylsulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptonoate hydrate (S-1452) and 5(Z-6-{(1R,2R,3R,4S)-3-(N-4-bromobenzenesulfonyl aminomethyl) bicyclo[2,2,1]heptane-2-yl)hex-5-enoic acid (ONO-NT-126), enhanced the cisplatin-induced apoptosis in each cell line. Acetyl-L-aspartyl-glutamyl-valyl-aspart-1-aldehyde (Ac-DEVD-CHO) inhibited cisplatin-induced apoptosis and enhancement of the apoptosis by TXA(2) blockade, but acetyl-L-tyrosyl-valyl-alanyl-aspart-1-aldehyde (Ac-YVAD-CHO) had no effect on the apoptosis. There was no difference in the interleukin-1 beta-converting enzyme (ICE) protease protein expression in either cell line. Cysteine protease p32(CPP32) protein expression was lower in PC-9/CBDP but was not changed by S-1452, cisplatin. or cotreatment with cisplatin and S-1452. Ice and Ced-3 homolog (ICH-IL) expression was significantly lower in PC-9/CDDP and was up-regulated by S-1452 or ONO-NT-126. These data suggest that ICH-1L might play a critical role in cisplatin-induced apoptosis and that TXA(2) blockade up-regulates ICH-1L protein expression. Overexpression of ICH-1L and treatment with cisplatin might result in an increase is apoptosis in NSCLC cell lines.