Abstract A299: Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells.
Notice bibliographique
Résumé
Abstract AML is a hematological malignancy for which the standard of care therapy has remained unchanged for almost 30 years. Novel therapeutic approaches are therefore urgently needed for the treatment of this heterogeneous disease. To identify new strategies for the treatment of AML, we screened a natural product library for compounds cytotoxic to AML cells and identified Deoxysappanone B 7,4’-dimethyl ether. Deoxysappanone B is a homoisoflavanoid compound extracted primarily from the dried heartwood of Caesalpinia sappan, a medicinal plant native to South-East Asia. However, anticancer activity of this compound has not been previously described and its molecular targets are largely unknown. In subsequent validation studies, Deoxysappanone B possessed anti-leukemic activity in 6 tested AML cell lines with nanomolar IC50s and was preferentially cytotoxic to primary AML cells and stem/progenitor cells over normal hematopoietic cells. To understand its mechanism of action, we performed chemo-genomic profiling of Deoxysappanone B in S. cerevisiae and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and lysosomes’ proton-pumping vacuolar (V)-ATPase as potential targets. We confirmed Deoxysappanone B's action as a microtubule inhibitor and localized its binding site near to that of colchicine via in-vitro tubulin polymerization and competitive binding assays. We also showed that Deoxysappanone B reversibly induces cell cycle arrest and cell death in a panel of AML cell lines as well as overcomes some mechanisms of resistance to vinca alkaloids. Validating the functional importance of tubulin as a target for Deoxysappanone B-mediated cell death, epidermoid carcinoma cells with a tubulin mutation were more resistant to Deoxysappanone B compared to their parental counterpart. In addition to inhibiting tubulin polymerization, Deoxysappanone B also increased lysosome acidity as measured by a V-ATPase enzymatic assay as well as staining with LysoSensor™ Yellow/Blue DND-160 and confocal microscopy. The sustained increase in lysosome acidity ultimately led to lysosomal disruption as evidenced by acridine orange staining. Supporting a tubulin-mediated effect on lysosomes, nocodazole, although not vinblastine, vincristine, paclitaxel or colchicine, produced a similar increase in lysosome acidity and lysosomal disruption. The effects on lysosomes were functionally relevant as pre-treatment with bafilomycin A1, a lysosomal V-ATPase inhibitor, partially abrogated the cytotoxic effect of Deoxysappanone B. Thus, our data provide insight into a novel mechanism of action of select microtubule inhibitors in the context of AML. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A299. Citation Format: Dannie Bernard, Marinella Gebbia, Swayam Prabha, Marcela Gronda, Neil MacLean, Xiaoming Wang, Rose Hurren, Mahadeo A. Sukhai, Eunice E. Cho, Morris F. Manolson, Alessandro Datti, Jeffrey Wrana, Rima Al-Awar, Ahmed Aman, Corey Nislow, Guri Giaever, Aaron D. Schimmer. Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A299.
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) | 0,000 | 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 ».