Abstract 3829A: Pantoprazole enhances the activity of chemotherapy for solid tumors by inhibition of autophagy.
Notice bibliographique
Résumé
Abstract Purpose: Resistance to anti-tumour agents is a major cause of treatment failure in patients with cancer. Luciani have shown that PPIs can augment the effects of chemotherapy in vitro and in vivo, most likely by modifying the acid-base balance across the cell membrane and/or of intracellular organelles such as lysosomes and endososmes. Endosomes are important intermediaries of the process of autophagy, a survival mechanism for stressed cells and a possible target for anticancer therapy. Here we evaluated the effect of pantoprazole (PTP) to modify cytotoxic effects of the commonly-used anticancer drug docetaxel (DOC) for cultured cells and for human tumour xenografts, to modify the distribution of biomarkers of activity of docetaxel in relation to tumour blood vessels and inhibit autophagy. Methods: Endosomal pH of cells was measured by fluorescence spectroscopy following exposure to the endosomal probe Lysosensor. Levels of autophagy were evaluated by quantifying the level of the LC3B protein in Western blots. Human prostate cancer PC3 cells were transfected with a construct where LC3B was linked to red (RFP) and green (GFP) fluorescent protein (mRFP-GFP-LC3) such that cells with high levels of autophagy stained red while those with low levels stained green. Cytotoxicity of DOC +/-PTP was evaluated in vitro by a colony-forming assay for PC3 parental cells, and for cells transfected with shRNAs to inhibit autophagy. Growth delay of three human xenografts in nude mice was evaluated following treatment with single or multiple doses of DOC+/- PTP. The distribution of drug effects in tumour sections in relation to blood vessels was quantified (at early intervals of ∼30 minutes) by γH2AX, a marker of DNA damage, and (at 24 hours) by cleaved caspase 3, a marker of apoptosis. Results: PTP increased endosomal pH and inhibited autophagy in a dose and time dependent manner. PTP was not cytotoxic when used alone but increased the cytotoxicity of DOC for cultured PC3 cells; the effects of PTP were reduced against genetically-modified cells that have reduced ability to undergo autophagy. Pre-treatment with PTP increased markedly the growth delay due to DOC of three different xengografts, especially after three treatments at weekly intervals, with minimal effects on DOC toxicity. Cellular effects of DOC evaluated by γH2AX and by cleaved caspase 3 decreased with increasing distance from tumour blood vessels, but were enhanced substantially by pre-treatment with PTP. There is less cell proliferation and marked reduction in hypoxia in xenografts generated from autophagy-deficient PC3 cells compared to PC3 wild type xenografts. Conclusions: Pantoprazole increases the therapeutic effectiveness of docetaxel in vitro and in vivo, and a potential mechanism is inhibition of autophagy. Docetaxel is the primary chemotherapy for men with metastatic castration resistant prostate cancer, and we plan a phase II study of PTP + DOC in such patients. Citation Format: Qian Tan, Anthony Joshua, Jasdeep Saggar, Man Yu, Carol M Lee, Marianne Koritzinsky, Bradly R Wouters, Ian F Tannock. Pantoprazole enhances the activity of chemotherapy for solid tumors by inhibition of autophagy. [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 3829A. doi:10.1158/1538-7445.AM2013-3829A
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) | 0,004 | 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 ».