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| Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines |
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| Author(s): Yamanaka T, Shiraki K, Sugimoto K, Ito T, Fujikawa K, Ito M, Takase K, Moriyama M, Nakano T, Suzuki A |
| Source: HEPATOLOGY Volume: 32 Issue: 3 Pages: 482-490 Published: SEP 2000 |
| Times Cited: 122 References: 52 |
| Abstract: TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2, and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. We investigated the expression of TRAIL-R- and TRAIL-induced apoptosis in human hepatocellular carcinomas (HCCs). TRAIL R1, -R2, and -R4 were expressed in 6 HCC cell lines examined, but TRAIL-R3 was expressed in only 2 of the 6 cell lines. In addition, immunohistochemical results revealed a high and prevalent expression of TRAIL-R1 and -R2 in human HCC tissues. Despite the expression of TRAIL-R1 and -R2, all 6 HCC cell lines showed resistance to TRAIL-induced apoptosis with no relation to nuclear factor kappa B (NF-kappa B) levels induced by TRAIL. TRAIL-induced death signal was inhibited with both decreased caspase-8 and caspase-3 activity. However, TRAIL induced significant apoptosis in the presence of a subtoxic level of actinomycin D, indicating that the TRAIL-induced apoptotic pathway is in place in these cell lines. In addition, we found that treatment with conventional chemotherapeutic agents, doxorubicin and camptothecin, dramatically augmented TRAIL-induced cytotoxicity in most of the HCC cell lines. Actinomycin D and camptothecin almost completely suppressed NF-kappa B induction by TRAIL, whereas doxorubicin had little effect. These results indicate that TRAIL, in combination with chemotherapeutic agents, may have therapeutic potential in the treatment of human HCC. |
| Document Type: Article |
| Language: English |
| Reprint Address: Shiraki, K (reprint author), Mie Univ, Sch Med, Dept Internal Med 1, 2-174, Tsu, Mie 5148507 Japan |
Addresses:
1. Mie Univ, Sch Med, Dept Internal Med 1, Tsu, Mie 5148507 Japan
2. Toray Ind Inc, Basic Res Labs, Kamakura, Kanagawa Japan
3. Daiichi Pharmaceut Co Ltd, Tokyo R&D Ctr, Basic Technol Res Lab, Projects Cell Death Res, Tokyo, Japan |
| Publisher: W B SAUNDERS CO, INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA |
| Subject Category: Gastroenterology & Hepatology |
| IDS Number: 350FV |
| ISSN: 0270-9139 |
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