Abstract | OBJECTIVES: METHODS: Two human GCT lines (COV434 and KGN) were treated with cisplatin or TRAIL, alone or in combination. The cytotoxic effects of each treatment were evaluated using a methyl tetrazolium salt (MTS) assay. Initiation of TRAIL-induced apoptosis was verified by PARP- and FLIP-cleavage. Overexpression and knockdown studies were conducted to evaluate the role of p53 in TRAIL-induced cell death. Real-time PCR was used for gene expression analysis of the TRAIL receptor dr5 and the pro-apoptotic bax following treatment with cisplatin. RESULTS: Treatment with TRAIL (100-200 ng/ml) led to a slight, but significant, loss of cell viability following an 18-h culture. This effect was enhanced following pre-treatment with cisplatin (25 microM) for 2 or 18 h. Moreover, pre-treatment with cisplatin decreased the maximal effective dose of TRAIL from 100 ng/ml to as low as 3 ng/ml in both cell lines. GCT lines overexpressing or deficient in p53 were used to determine the requirement for p53 on TRAIL-induced apoptosis. While the level of p53 expression enhanced both the death-inducing and TRAIL-sensitizing effects of cisplatin, TRAIL-induced cell death was found to occur independent of p53. CONCLUSIONS: These data suggest that the efficacy of cisplatin in GCT cells can be enhanced through combinatorial treatment with TRAIL. This result is due to both p53-dependent ( cisplatin) and -independent (TRAIL) mechanisms. Combinatorial treatment of GCTs with cisplatin and TRAIL may provide an efficacious addition to cisplatin-based regimens.
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Authors | Dori C Woods, Claudia Alvarez, A L Johnson |
Journal | Gynecologic oncology
(Gynecol Oncol)
Vol. 108
Issue 3
Pg. 632-40
(Mar 2008)
ISSN: 1095-6859 [Electronic] United States |
PMID | 18191995
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Antineoplastic Agents
- TNF-Related Apoptosis-Inducing Ligand
- Cisplatin
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Topics |
- Antineoplastic Agents
(administration & dosage, pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
(drug effects)
- Cisplatin
(administration & dosage, pharmacology)
- Female
- Granulosa Cell Tumor
(drug therapy, pathology)
- Humans
- Ovarian Neoplasms
(drug therapy, pathology)
- TNF-Related Apoptosis-Inducing Ligand
(administration & dosage, pharmacology)
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