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Synergistic induction of apoptosis by the combination of trail and chemotherapy in chemoresistant ovarian cancer cells.
Gynecol Oncol. 2001 Jun; 81(3):380-90.GO

Abstract

OBJECTIVES

The aim of this study was to investigate whether TNF-related apoptosis-inducing ligand (TRAIL) alone or in combination with chemotherapy could induce apoptosis in ovarian cancer cells resistant to chemotherapy.

METHODS

Twelve chemoresistant epithelial cancer cell lines were treated with each chemotherapeutic drug alone (cisplatin, doxorubicin, or paclitaxel), TRAIL alone, or the combination. Toxicity was assessed using the MTS assay. To assess whether growth inhibition was due to apoptosis, TUNEL assay, caspase activation (measured by caspase-3 and PARP cleavage), and the sub G0/G1 fraction of cells were measured. Synergism was confirmed by fractional inhibition and dose-effect analysis. Expression of death and decoy receptors was studied by immunoblotting and an RNase protection assay. Statistical comparison of means was performed using Student's t test.

RESULTS

The majority of the chemoresistant cells were also resistant to TRAIL alone. In contrast, the combination of TRAIL and chemotherapy resulted in a significant growth inhibition over a wide range of concentrations. This interaction was synergistic by dose-effect analysis. Flow cytometry demonstrated a significant increase in the fraction of apoptotic cells by the combination compared to each reagent alone. A significant enhancement in caspase and PARP cleavage was observed upon treatment with the combination. Finally, no correlation between induction of apoptosis and level of death receptors was found.

CONCLUSIONS

The data suggest that almost all the ovarian cancer cells, which are resistant to chemotherapy, are also resistant to TRAIL. The combination of TRAIL and chemotherapy overcomes this resistance in a synergistic fashion by triggering caspase-mediated apoptosis. The combination of TRAIL and chemotherapy could be useful as a therapy for chemoresistant ovarian cancers.

Authors+Show Affiliations

Genetics Department, National Cancer Institute, Bethesda, Maryland 20889, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11371126

Citation

Cuello, M, et al. "Synergistic Induction of Apoptosis By the Combination of Trail and Chemotherapy in Chemoresistant Ovarian Cancer Cells." Gynecologic Oncology, vol. 81, no. 3, 2001, pp. 380-90.
Cuello M, Ettenberg SA, Nau MM, et al. Synergistic induction of apoptosis by the combination of trail and chemotherapy in chemoresistant ovarian cancer cells. Gynecol Oncol. 2001;81(3):380-90.
Cuello, M., Ettenberg, S. A., Nau, M. M., & Lipkowitz, S. (2001). Synergistic induction of apoptosis by the combination of trail and chemotherapy in chemoresistant ovarian cancer cells. Gynecologic Oncology, 81(3), 380-90.
Cuello M, et al. Synergistic Induction of Apoptosis By the Combination of Trail and Chemotherapy in Chemoresistant Ovarian Cancer Cells. Gynecol Oncol. 2001;81(3):380-90. PubMed PMID: 11371126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergistic induction of apoptosis by the combination of trail and chemotherapy in chemoresistant ovarian cancer cells. AU - Cuello,M, AU - Ettenberg,S A, AU - Nau,M M, AU - Lipkowitz,S, PY - 2001/5/24/pubmed PY - 2001/6/29/medline PY - 2001/5/24/entrez SP - 380 EP - 90 JF - Gynecologic oncology JO - Gynecol Oncol VL - 81 IS - 3 N2 - OBJECTIVES: The aim of this study was to investigate whether TNF-related apoptosis-inducing ligand (TRAIL) alone or in combination with chemotherapy could induce apoptosis in ovarian cancer cells resistant to chemotherapy. METHODS: Twelve chemoresistant epithelial cancer cell lines were treated with each chemotherapeutic drug alone (cisplatin, doxorubicin, or paclitaxel), TRAIL alone, or the combination. Toxicity was assessed using the MTS assay. To assess whether growth inhibition was due to apoptosis, TUNEL assay, caspase activation (measured by caspase-3 and PARP cleavage), and the sub G0/G1 fraction of cells were measured. Synergism was confirmed by fractional inhibition and dose-effect analysis. Expression of death and decoy receptors was studied by immunoblotting and an RNase protection assay. Statistical comparison of means was performed using Student's t test. RESULTS: The majority of the chemoresistant cells were also resistant to TRAIL alone. In contrast, the combination of TRAIL and chemotherapy resulted in a significant growth inhibition over a wide range of concentrations. This interaction was synergistic by dose-effect analysis. Flow cytometry demonstrated a significant increase in the fraction of apoptotic cells by the combination compared to each reagent alone. A significant enhancement in caspase and PARP cleavage was observed upon treatment with the combination. Finally, no correlation between induction of apoptosis and level of death receptors was found. CONCLUSIONS: The data suggest that almost all the ovarian cancer cells, which are resistant to chemotherapy, are also resistant to TRAIL. The combination of TRAIL and chemotherapy overcomes this resistance in a synergistic fashion by triggering caspase-mediated apoptosis. The combination of TRAIL and chemotherapy could be useful as a therapy for chemoresistant ovarian cancers. SN - 0090-8258 UR - https://www.unboundmedicine.com/medline/citation/11371126/Synergistic_induction_of_apoptosis_by_the_combination_of_trail_and_chemotherapy_in_chemoresistant_ovarian_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(01)96194-3 DB - PRIME DP - Unbound Medicine ER -