Abstract 2529: The anti-malarial agent Mefloquine preferentially demonstrates pre-clinical activity in leukemia and myeloma cells through STAT1-induced reactive oxygen species production
Notice bibliographique
Résumé
Abstract Off patent drugs with previously unrecognized anti-leukemia activity can be rapidly repurposed for this new indication, given their prior safety and toxicity testing. By screening a group of anti-malarial compounds for anti-cancer activity, we identified mefloquine, a quinoline licensed in oral formulation for the treatment of malaria. As an anti-cancer agent, we demonstrated that mefloquine decreased the viability of 9/9 leukemia cell lines with an LD50 <7.5 uM, and 9/9 myeloma cell lines with an LD50 <5.0 uM. Furthermore, mefloquine demonstrated induced cell death in primary AML samples (n = 3; LD50 <7.5 uM), but not normal peripheral blood stem cells. Given its in vitro activity, we evaluated the effects of oral mefloquine in mouse xenograft models of leukemia. Sublethally irradiated SCID mice were injected subcutaneously with OCI-AML2 or K562 human leukemia cells or MDAY-D2 murine leukemia cells, and treated with 50 mg/kg mefloquine, or vehicle alone by oral gavage. Oral mefloquine decreased tumor weight and volume in all 3 mouse models without toxicity. Mechanistically, mefloquine induced reactive oxygen species (ROS) in leukemia cells at times preceding and concentrations associated with cell death. Blockade of ROS by N-acetyl-L-cysteine (NAC) abrogated mefloquine sensitivity, suggesting that mefloquine-mediated cell death in AML was ROS-dependent. To further understand the mechanism of mefloquine-mediated cytoxicity, whole genome gene expression oligonucleotide array analysis of AML cells treated with mefloquine was conducted. The gene expression pattern of cells treated with mefloquine strongly resembled gene signatures associated with activated Toll-like receptor and interferon response pathways. STAT1 and NF-κB, both downstream transcription factor components of TLR-IFN signaling, were activated, as were downstream targets IRF1, IRF7 and IL-8, at times that preceded mefloquine-induced cell death. Gene expression changes were validated by Q-RT-PCR, and are potential biomarkers of mefloquine activity in cells. This pathway appears functionally important for mefloquine-mediated cell death, as cell lines defective for STAT1 signaling components showed decreased cell death after mefloquine treatment. These lines also showed decreased ability to generate ROS in response to mefloquine treatment, suggesting that mefloquine-induced ROS was produced through a STAT1-dependent mechanism. Taken together, our data demonstrate that the anti-malarial mefloquine displays significant pre-clinical activity in leukemia and myeloma cells, likely through a STAT1-dependent induction of ROS that is triggered by activation of the TLR-IFN cytokine axis in cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2529.
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) | 0,005 | 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 ».