Abstract 1688: Autophagy inhibition enhances the antitumor effects of combretastatin A4 phosphate (CA4P).
Notice bibliographique
Résumé
Abstract Vascular disruptive agents such as CA4P cause an acute shutdown of the tumor vasculature resulting in metabolic stress and central tumor necrosis. However, tumor recurrence may ensue from peripheral tissue that survives the vascular insult because of less severe metabolic conditions (i.e, viable rim). Autophagy is an evolutionarily conserved cellular response to stress that is either enabling cell survival or mediating cell death, depending on the circumstances. During cancer therapy, autophagy is usually thought to contribute to cell survival and thus to therapeutic resistance. Hence, we hypothesized that autophagy inhibition would amplify the antitumor effects of CA4P by lowering the threshold of peripheral tumor cells to withstand the metabolic stress due to CA4P administration. Since available pharmacological autophagy inhibitors lack specificity, we established pairs of isogenic autophagy-defective (ATG4BC74A) and autophagy-competent (vector control, i.e., mstr) prostate cancer cells by means of retrovirally transducing PC-3 and C4-2 human prostate cancer cells with ATG4BC74A (an inactive and dominant-negative mutant of the autophagy related gene atg4B). These paired cell lines were characterized in vitro (autophagy and proliferation assays in cells exposed to CA4P), and PC-3 xenograft tumors were grown subcutaneously in mice subjected to CA4P (100 mg/kg ip). We collected tumors after 24 hours and 1 week for cryosectioning and preparation of protein lysates. To document the autophagy status in tumors, lysates were analysed by LC-3 Western blotting. The degree of necrosis and senescence in tissue sections was measured by H&E and senescence-associated β-galactosidase histochemistry, respectively. Microvessel density was assessed by CD31 immunofluorescence. CA4P associated inhibition of proliferation was not influenced by the autophagy status of PC-3 and C4-2 (CA4 IC50 ∼7 nmol/L for both PC-3 and C4-2). We also observed similar growth kinetics of PC-3 ATG4BC74A and mstr tumors in control and CA4P treated mice. Furthermore, we documented a comparable decrease in CD31 microvessel density 24 hours after C4AP administration in PC-3 ATG4BC74A and mstr xenografts, a change that was reversed 1 week following C4AP treatment. However, CA4P caused more extensive central tumor necrosis as well as a larger number of senescent cells in autophagy-deficient PC-3 tumors both 24 hours and 1 week following CA4P therapy. In summary, autophagy inhibition amplifies the necrosis- and senescence-inducing properties of CA4P. Further investigations are aiming at assessing the impact of the autophagy status of PC-3 tumors on CA4-mediated apoptosis and hypoxia. We also plan to expand our analyses to the C4-2 model. Finally, we are currently studying if combined CA4P therapy and autophagy inhibition results in improved long-term tumor control. Such combination therapy could be rapidly translated into the clinic. Citation Format: Van C. Hoang, Annabelle Chow, Urban Emmenegger. Autophagy inhibition enhances the antitumor effects of combretastatin A4 phosphate (CA4P). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1688. doi:10.1158/1538-7445.AM2013-1688
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».