Abstract A061 Overcoming chemotherapic resistance caused by β3-AR in Ewing’s sarcoma with the receptor’s antagonist
Notice bibliographique
Résumé
Abstract Introduction: Ewing's sarcoma (ES) is a highly malignant tumor that commonly occurs in children and adolescents. The therapeutic strategy is based on a multi-drug chemotherapy regimen, in combination with radiotherapy and surgery. Unfortunately, ES cells exhibit a high sensitivity to rapid changes in intracellular redox environment resulting in an elevated incidence of drug resistance. In recent years, β3-adrenergic receptor (β3-AR) has gained growing attention due to its implication in tumor onset, progression and metastasis, alongside its physiological functions. Indeed, it has been found to be overexpressed in various tumors, especially pediatric malignancies, including ES. β3-adrenergic receptor acts as the main regulator of the cellular response to redox environment, ultimately by influencing the expression of UCP2, well-known transporter that decreases mitochondrial activity and ROS content. The β3-AR antagonist, SR59230A (SR), demonstrated to reverted these effects. Therefore, we exploited the effects of SR59230A in ES cells that increases the intracellular ROS content and enhancing their sensitivity to treatment with doxorubicin (DOX) drug, which among its functions also influences UCP2 protein. As a result, the combination of both compounds may represent a putative novel therapeutic strategy able to overcome drug resistance in ES cancer. Aim: In the attempt of overcoming chemotherapy resistance in Ewing’s sarcoma, we studied the effects of DOX compound in combination with SR, the main β3-AR antagonist, which enhances the cell’s sensitivity to treatments. Methods: We performed proliferation assays to asses IC50 of both compounds in A673 cells. After 3h and 24h of treatment with DOX and SR, alone and in combination, the ROS levels and mitochondrial membrane potential were evaluated using flow cytometry analysis. The metabolic profile of A673 in the same conditions was measured using Seahorse XF Analyzer. The data was confirmed by Western Blotting investigation. Statistical analysis was performed using one-way and two-way ANOVA with Tukey’s post-hoc test (*p<0.05). Results and conclusions: Our data shows an increase in ROS content in A673 cells after 3h and 24h of treatment with DOX and SR in combination compared to treatments with the single drug, in accordance with the modulation of UCP2 exerted by the drugs. This result is confirmed by western blot analysis, which shows an increased level of expression of SOD2 after 24h of treatment with a combination of the compounds. The metabolic real time analysis of A673 after 3h and 24h with the same treatments shows a decreased in ATP mitochondrial production, supporting the flow cytometry investigation that demonstrates a decrease in mitochondrial membrane potential after 3h of treatment with both compounds and with SR alone compared to control. In conclusion the β3-AR/UCP2 axis decreased mitochondrial activity by reducing ATP synthesis and mitochondrial ROS content and this effect is reverted by β3-AR antagonist, allowing to overcome drug resistance in combination treatments with DOX. Citation Format: Megan Lotti, Rachele Amato, Maria Ascone, Cristina Banella, Francesco Carrozzo, Amada Pasha, Annalisa Tondo, Maura Calvani. Overcoming chemotherapic resistance caused by β3-AR in Ewing’s sarcoma with the receptor’s antagonist [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A061.
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».