Abstract 491: Selective killing of oncogenically transformed cells by arsenic trioxide and trolox
Notice bibliographique
Résumé
Abstract Background: A major disadvantage of cytotoxic chemotherapy is the difficulty in selectively targeting tumor cells. Although arsenic trioxide (ATO) is an effective therapy in acute promyelocytic leukemia (APL), its use in solid tumors is limited by the toxicity observed at concentrations required to induce apoptosis in non-APL cells. We previously found that trolox, a vitamin E derivative, enhances ATO-induced apoptosis in APL cells, while simultaneously protecting normal cells. The objective of the current study is to understand the mechanism(s) by which trolox switches from cytoprotective to cytotoxic upon the oncogenic transformation of cells. Materials and methods: This study was conducted using two isogenic models: mouse embryonic fibroblast (MEFs) and MEFs stably-transfected with either E6/E7 or E1A/Ras oncogenes. Apoptosis was assessed via staining with Propidium Iodide (Cell Signaling) followed by FACS analysis. Cells were treated with various concentrations of ATO alone or in combination with 100μM trolox for 48 hours. SubG0 cell population results were obtained by staining the cells with PI, followed by analysis using CellQuest software. Mitochondrial ROS levels were measured with MitoSox (Life Technologies), followed by FACS analysis. Cells were treated with 5μM ATO alone or in combination with 100μM trolox for 18 hours. Mitochondrial fluorescence was examined by staining the cells with MitoSOX (Life Technologies). For the visualization and enumeration of mitochondria, cells were examined with Transmission Electron Microscopy (TEM). Intracellular pictures were taken with TEM at FEMR, McGill University. Changes in cellular metabolism were measured with an XF96 Extracellular Flux Analyzer (Seahorse Bioscience). Results: In both the E6/E7 and E1A/Ras models, trolox enhances ATO-induced death. In contrast, trolox has a protective effect from ATO toxicity in their untransformed counterparts. In the transformed cell lines, cell death correlates with enhanced formation of mitochondrial superoxide when treated with arsenic in combination with trolox. The functionality of mitochondria is closely linked to their structure. Preliminary analysis of TEM images indicates that mitochondrial structural integrity in transformed cells deteriorates when treated with ATO in combination with trolox. Finally, these results are supported by changes in cellular metabolisms in the transformed cell lines. Conclusion: Transformed cells are more sensitive to cytotoxicity induced by arsenic trioxide in combination with trolox than their wild-type counterparts. We hypothesize that the predominant mechanism of action by which transformed cells are sensitized to the actions of trolox and ATO is due to a dysfunction of mitochondrial activity. The results of this study will provide a means to expand the therapeutic spectrum of ATO beyond APL by enhancing tumor selectivity and protecting normal tissue from toxicity. Citation Format: Genevieve G. J. Redstone, Jessica N. Nichol, Brandon Faubert, Russell G. Jones, Koren K. Mann, Wilson H. Miller. Selective killing of oncogenically transformed cells by arsenic trioxide and trolox. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2014-491
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
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 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| 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 ».