Abstract A51: Identification of compounds targeting human leukemia stem cells
Notice bibliographique
Résumé
Abstract Over the past 15 years, research has conclusively shown the existence of a rare population of cancer cells, termed cancer stem cells, in leukemia, brain, colon, and breast cancers. These cells are biologically distinct from bulk cells and are the only cells able to initiate and sustain the disease. Recent experiments indicate that standard chemotherapy for leukemia is less effective against leukemia stem cells (LSC) than bulk leukemia cells and typically does not spare normal hematopoietic stem cells (HSC) and progenitor cells leading to myelosuppression. Therefore, a new paradigm is needed to develop cancer therapeutics that effectively eradicate the disease by targeting the LSC. Here, we sought to identify compounds that selectively target LSC but not normal HSC by using populations enriched for LSC and HSC, instead of traditional cancer cell lines, in high-throughput screening of three libraries of small chemicals comprising over 4000 known bioactive, off-patent, and natural compounds. Recently, we generated human leukemia cells by direct transformation of normal human primitive hematopoietic cells (Lin- CB) with leukemogenic fusion oncogenes. These cells exhibit features of LSC, such as hierarchical organization, engraftment of NOD/SCID mice, and a differentiation block. As a proof of principle, we screened two leukemia cell lines using a simple cell-growth inhibition assay. 76 compounds were scored as positive against both lines. Numerous anti-cancer therapeutics (paclitaxel, etoposide, and vincristine), general cytotoxic agents (brefeldin), and the digitalis family of ion pump inhibitors (digoxin, ouabain) were identified. Since LSC share some pathways with normal HSC, we counter-screened potential hits on normal HSC and progenitor cells and identified only 10 compounds. Three of the 10 compounds targeted LSC, ciclopirox olamine, etoposide, and kinetin riboside (KR). KR was effective on primary AML and CML at levels similar to the AML chemotherapeutics cytarabine and mitoxantrone. Kinetin riboside induced apoptosis in phenotypic CD34+CD38- LSC, but not CD34+CD38- HSC similar to the anti-LSC compound parthenolide. In contrast to parthenolide, treatment of primary AML cells with kinetin riboside inhibited engraftment in NOD/SCID mice for 2 of 4 samples. The second compound, ciclopirox olamine, targeted LSC and not HSC, by chelating intracellular iron and inhibited the ribonucleotide reductase enzyme. Ciclopirox olamine is a clinically used antifungal and could be rapidly repurposed for treating leukemia. The third compound, etoposide, was effective in vitro on 29% (15 of 51) of primary AML and 67% (8 of 12) of CML patient cells. Etoposide inhibited NOD/SCID engraftment of three responsive AML samples, but not three non-responsive samples, indicating etoposide targeted the LSC in a subset of patients. Together, these screens have identified multiple anti-LSC compounds and represent a new paradigm for drug screening against LSC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A51.
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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 ».