Chaetocin antileukemia activity against chronic myelogenous leukemia cells is potentiated by bone marrow stromal factors and overcomes innate imatinib resistance
Notice bibliographique
Résumé
Chronic myelogenous leukemia (CML) is maintained by a minor population of leukemic stem cells (LSCs) that exhibit innate resistance to tyrosine kinase inhibitors (TKIs) targeting BCR-ABL. Innate resistance can be induced by secreted bone marrow stromal cytokines and growth factors (BMSFs) that protect CML-LSCs from TKIs, resulting in minimal residual disease. Developing strategies to eradicate innate TKI resistance in LSCs is critical for preventing disease relapse. Cancer cells balance reactive oxygen species (ROS) at higher than normal levels, promoting their proliferation and survival, but also making them susceptible to damage by ROS-generating agents. Bcr-Abl increases cellular ROS levels, which can be reduced with TKI inhibitors, whereas, BMSFs increase ROS levels. We hypothesized that BMSF-mediated increases in ROS would trigger ROS damage in TKI-treated CML-LSCs when exposed to chaetocin, a mycotoxin that imposes oxidative stress by inhibiting thioredoxin reductase-1. Here, we showed that chaetocin suppressed viability and colony formation, and induced apoptosis of the murine hematopoietic cell line TonB210 with and without Bcr-Abl expression, and these effects were potentiated by BMSFs. In contrast, imatinib activities in Bcr-Abl-positive TonB210 cells were inhibited by BMSFs. Further, BMSFs did not inhibit imatinib activities when TonB210 cells expressing Bcr-Abl were cotreated with chaetocin. Chaetocin showed similar activities against LSC-enriched CML cell populations isolated from a murine transplant model of CML blast crisis that were phenotypically negative for lineage markers and positive for Sca-1 and c-Kit (CML-LSK). BMSFs and chaetocin increased ROS in CML-LSK cells and addition of BMSFs and chaetocin resulted in higher levels compared with chaetocin or BMSF treatment alone. Pretreatment of CML-LSKs with the antioxidant N-acetylcysteine blocked chaetocin cytotoxicity, even in the presence of BMSFs, demonstrating the importance ROS for chaetocin activities. Chaetocin effects on self-renewal of CML-LSKs were assessed by transplanting CML-LSKs into secondary recipients following ex vivo exposure to chaetocin, in the presence or absence of BMSFs. Disease latency in mice transplanted with CML-LSKs following chaetocin treatment more than doubled compared with untreated CML-LSKs or BMSFs-treated CML-LSKs. Mice transplanted with CML-LSKs following chaetocin treatment in the presence of BMSFs had significantly extended survival time compared with mice transplanted with CML-LSKs treated with chaetocin alone. Our findings indicate that chaetocin activity against CML-LSKs is significantly enhanced in the presence of BMSFs and suggest that chaetocin may be effective as a codrug to complement TKIs in CML treatment by disrupting the innate resistance of CML-LSKs through an ROS dependent mechanism.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 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 ».