Abstract 3233: Targeting system xc- in breast cancer cells: Development of novel therapeutics
Notice bibliographique
Résumé
Abstract Cancer-induced bone pain is a major palliative condition suffered by many afflicted with breast cancer. With current anti-cancer therapeutics prolonging the lives of these patients without eradicating the disease itself, quality of life concerns predominate patient care. A potential mechanism implicates glutamate, and specifically the glutamate-cystine antiporter called system xc-. Due to the accelerated metabolism of cancer cells, this transporter (xCT) is upregulated to supply the cell with adequate cysteine for detoxification of reactive oxygen species via glutathione (GSH) synthesis. We conducted a high-throughput screening of 30,000 compounds to identify novel small molecules capable of reducing glutamate release from MDA-MB-231 cells. Glutamate release was quantified using Amplex Red fluorometric assay after 48 hours incubation with test compounds. Compounds providing the greatest effect were: 4-[2-(Dipropylamino)ethyl]-1,2-benzenediol, SKF 38393, Capsazepine and SPB 05855. Follow-up entailed confirmation of screening results (i.e. inhibition of glutamate secretion) in a dose dependent manner (0-200uM). GSH content of treated cells was also analyzed as it's production is linked to xCT activity. Intracellular GSH levels were analyzed in cell lysates using DNTB. In addition, to further explore mode of action of these compounds, we cloned 2.6 kilobase pairs (-2329 to +278 bp) of the human xCT promoter region from genomic DNA isolated from MDA-MB-231 breast cancer cells. Four truncations were also generated by PCR. Full length and truncated clones were transferred into a luciferase reporter gene construct (PGL3-Basic). This acted as a tool to test whether any of these compounds inhibit glutamate release through transcriptional regulation of xCT. MDA-MB-231 cells were transiently co-transfected with the dual luciferase system and subsequently treated with compounds. Glutamate release data confirmed the results of most positive hits but revealed that SPB 05855 did not meet the original criteria, as it had no effect on inhibition of glutamate release when re-tested. Compound cytotoxicity was assessed using crystal violet staining and dose-response data indicated that a concentration of 50 µM was the highest effective dose that did not result in cytotoxicity for all confirmed compounds. GSH results indicate that only SKF 38393 reduces total GSH levels in a dose-dependent manner. Promoter activity revealed that, of the four compounds, only SKF 38393 significantly affected promoter activity resulting in a 30% reduction in luciferase production. These experiments indicate a series of potent compounds that inhibit glutamate release and have the potential for development into novel therapeutics aimed at the treatment of cancer-induced bone pain. Citation Format: Jennifer Fazzari, Hanxin Lin, Katja Linher-Melville, Gurmit Singh. Targeting system xc- in breast cancer cells: Development of novel therapeutics. [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 3233. doi:10.1158/1538-7445.AM2014-3233
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 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) | 0,002 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».