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 A2 (TXA2) blockade on cisplatin-induced apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cisplatin induced apoptosis in PC/9 and PC-9/CDDP in a dose-dependent manner. Treatment with specific TXA2 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 TXA2 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-1beta-converting enzyme (ICE) protease protein expression in either cell line. Cysteine protease p32(CPP32) protein expression was lower in PC-9/CDDP but was not changed by S-1452, cisplatin, or cotreatment with cisplatin and S-1452. Ice and Ced-3 homolog (ICH-1L) 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 TXA2 blockade up-regulates ICH-1L protein expression. Overexpression of ICH-1L and treatment with cisplatin might result in an increase in apoptosis in NSCLC cell lines.
The Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
M
M
Fujimura
K
K
Kasahara
H
H
Shirasaki
U
U
Heki
K
K
Iwasa
A
A
Ueda
T
T
Matsuda
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D053143:Caspase 2; D020169:Caspases / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; D011448:Prostaglandin Antagonists; C056566:S 145; C067520:ONO-NT 126; D013928:Thromboxane A2; D053143:Caspase 2; D020169:Caspases; D002945:Cisplatin