Abstract 4405: The novel allosteric Akt inhibitor, MK-2206, synergizes with gefitinib against human glioma cells via promoting the switch from autophagy to apoptosis
Notice bibliographique
Résumé
Abstract Gefitinib, a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to induce autophagy as well as apoptosis in tumor cells. This drug, in addition to being used for treatment of patients with non-small cell lung cancer, has also been in clinical trials for treating other types of cancer, including malignant brain tumors. However, the mechanism and signaling pathways mediating the gefitinib-induced tumor cell death, and the approach to enhancing the therapeutic efficacy of this drug against cancer, remain to be fully investigated. To explore the ways that can maximize the efficacy of gefitinib, in the current study we determined whether MK-2206, a potent allosteric small-molecule inhibitor of Akt currently in Phase I trials in patients with solid tumors, could reinforce the cytocidal effect of gefitinib against glioma, the most common form of brain cancer. We found in human glioma cell lines, LN229 and T98G, that both gefitinib and MK-2206 induced apoptosis and reduced the level of phosphorylation of Akt in a dose-dependent manner, indicating that these agents may induce apoptosis by inhibiting the Akt-mediating anti-apoptotic pathways. Co-treatment with gefitinib and MK-2206 increased the cytotoxicity of gefitinib in the glioma cells, and the Compusyn synergism/antagonism analysis showed that MK-2206 acted synergistically with gefitinib. Apoptosis assay (Annexin V staining) demonstrated that in the presence of MK-2206, there was a significant increase in apoptotic cell death in glioma cells treated with gefitinib, in comparison with the cells treated with gefitinib alone. Survivin, a member of inhibitor of apoptosis protein (IAP) family and a downstream player of the Akt pathway, was decreased by the combination treatment. MK-2206 also augmented the autophagy-inducing effect of gefitinib, as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by silencing of the key autophagy gene, beclin 1, further increased the cytotoxicity of the combination treatment of gefitinib with MK-2206, suggesting that autophagy induced by these agents plays a cytoprotective role. Notably, at 48 hours following the combination treatment, the level of LC3-II began to decrease but the accumulation of Bim, a pro-apoptotic BH3-only protein, was elevated, suggesting a switch from autophagy to apoptosis. Study of the precise molecular mechanism underlying this cross-talk between autophagy and apoptosis is still in progress. Based on the synergistic effect of MK-2206 on gefitinib observed in this study, the combination of these two drugs may be utilized as a new therapeutic regimen for malignant glioma. 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 4405. doi:10.1158/1538-7445.AM2011-4405
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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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».