Abstract NTOC-086: PAC–1 COMBINATION WITH TRAIL ENHANCES APOPTOSIS IN CELL–LINE AND PRIMARY CULTURED ADULT GRANULOSA CELL TUMOUR CELLS
Notice bibliographique
Résumé
Abstract BACKGROUND: Granulosa cell tumour (GCT) constitutes ~5% of ovarian neoplasms. Surgery remains the primary treatment modality due to a generally poor response to chemotherapy in GCT patients. Procaspase activating compound-1 (PAC1) is a small-molecule drug shown in vitro to sequester inhibitory zinc ions from the Caspase-3 (CASP3) zymogen allowing CASP3 to automature and execute apoptosis. PAC1 has demonstrated safety and efficacy in vivo against several cancers and is currently in Phase I trials for advanced malignancies. TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptosis ligand that can bind membrane-bound death receptors. This binding triggers the extrinsic apoptotic pathway resulting in activation of CASP3 to execute its proteolytic role and programmed cell death. TRAIL has been found to induce apoptosis selectively in cancer cells in vitro and in vivo, and has been well tolerated in human patients. We hypothesise that combining PAC1 activation of CASP3 with induction of apoptotic signaling by exogenous TRAIL will significantly heighten biologic effect, reduction of disease, and that these effects will be obtained at doses lower than those required by either agent alone. Here we report on in vitro experiments in support of this hypothesis, suggesting that combining PAC1 with TRAIL may be effective therapy for treatment of GCT. METHODS: The GCT cell line KGN was treated in vitro with a 6-log range of PAC1 concentration for 48 hours to establish a dose-response curve (using a real-time cell analyzer, RTCA). In parallel, KGN cells were treated with a 6-log range of TRAIL concentration to establish its dose-response curve. Calculated EC50 values were then used for both PAC1 (20 μM) and TRAIL (10 ng/mL) to evaluate the biologic response of simultaneous treatment with PAC1 and TRAIL, and TRAIL delayed 24 hours after PAC1 treatment (using resazurin viability assay and RTCA). Separately, cells from fresh primary and recurrent tumour samples were cultured in vitro for 5 days, then treated with PAC1 (20 μM), TRAIL (10 ng/mL), or the combination, and finally assayed for viability and caspase 3/7 activity 48 and 72 hours later. RESULTS: Dose-response assays indicate treatment with PAC1 strongly reduces viability of KGN cells compared to untreated control (p<0.05) in a dose-dependent manner and treatment with PAC1 alone significantly reduced viability compared to untreated control (p<0.05). Similar assays with TRAIL only reduced viability of KGN cells at the highest concentration tested (1 µg/mL). The assays also suggest a ~24 hour delay in PAC1 reduction of GCT viability while TRAIL appears to display a time-limited response. Combination treatment was assessed using calculated EC50 concentrations for both PAC1 (20 µM) and TRAIL (10 ng/mL). Assays for both KGN and patient-derived primary GCT cells tested each drug alone, both drugs applied concurrently and TRAIL applied 24 hours after PAC1. Combination of PAC1 with TRAIL was dramatically more cytotoxic than TRAIL or PAC1 treatment alone (p<0.05) CONCLUSION: Combining CASP3 activator PAC1 with apoptosis-inducing agents may be an effective strategy for treatment of GCT and warrants preclinical assessment. Citation Format: Powel Crosley; Kate Agopsowicz; Marjut Pihlajoki; Markku Heikinheimo; Anniina Färkkilä; Mary Hitt. PAC–1 COMBINATION WITH TRAIL ENHANCES APOPTOSIS IN CELL–LINE AND PRIMARY CULTURED ADULT GRANULOSA CELL TUMOUR CELLS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-086.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».