Abstract 5360: Differential induction of the anti-oxidant response by arsenic trioxide and darinaparsin in leukemic cells
Notice bibliographique
Résumé
Abstract Darinaparsin (DAR) is a significantly more potent arsenical than arsenic trioxide (ATO) at mediating apoptosis in various malignant cell lines and is highly active against Acute Promyelocytic Leukemia (APL) cells (NB4). The mechanisms behind DAR's increased efficacy versus ATO remain to be elucidated. We previously reported that DAR triggers apoptosis by inducing cellular responses that do not completely overlap with ATO (Diaz et al. Leukemia). Oxidative damage has been postulated to be a key mechanism by which arsenicals initiate the apoptotic process. Consistent with its increased cytotoxicity, we observed that DAR induces superoxide (O2·−) and hydrogen peroxide (H2O2), as shown respectively by hydorethidine and dichloro-dihydro-fluorescein staining quantified by flow cytometry. In response to oxidative stress, cells induce an arsenal of protective proteins of which HO-1 (heme oxygenase-1), NQO1 (NAD(P)H:quinone oxidoreductase), TrxR1 (thioredoxin-reductase-1) and γGCS (glutamyl cysteine synthetase) are well recognized members. We therefore studied the expression of these stress response proteins after ATO and DAR treatment. As expected, we observed a significantly higher increase in NQO1, TrxR1 and γGCS mRNA and protein levels as assessed by Western Blot and quantitative real PCR, with DAR than with ATO. However, HO-1 expression was not induced by DAR. Nrf2 is a transcription factor that mediates the expression of key protective enzymes through antioxidant response elements (AREs). AREs have been identified in the regulatory regions of genes encoding detoxification enzymes and other cytoprotective proteins, including NQO1, TrxR1, γGCS, and HO-1. Nucleo-cytoplasmic fractionation followed by Western Blot show that both compounds induce Nrf2 translocation to the nucleus. Transcriptional regulation of these detoxifying enzymes involves a competition between the activator Nrf2 and the repressor Bach1 for interaction with their AREs. Accordingly, ChIP assays demonstrate that Bach1 is released and Nrf2 is recruited to the HO-1 ARE in ATO treated cells but not in cells treated with DAR. HO-1's widely reported cytoprotective effects in vitro and in vivo have been related to the generation of the antioxidants biliverdin and bilirubin. In order to elucidate whether the lack of HO-1 expression contributes to the increased efficacy of DAR, we examined the response to ATO and DAR in co-treatment with OB-24, a recently developed HO-1 inhibitor. As indicated by Propidium Iodide staining followed by flow cytometry analysis, pharmacological inhibition of HO-1 increased ATO toxicity but has no significant effect on DAR induced apoptosis. We therefore hypothesize that the increased efficacy of DAR versus ATO might be partially due to the absence of HO-1 up-regulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5360. doi:10.1158/1538-7445.AM2011-5360
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) | 0,002 | 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 ».