Abstract 3809: Modulation of MRP1 activity reverses chemotherapy resistance in adult cancer cells
Notice bibliographique
Résumé
Abstract Multidrug resistance protein 1 (MRP1) is an ATP-dependent efflux pump that extrudes chemotherapeutic drugs from cancer cells, preventing their intracellular accumulation and thus their efficacy. MRP1 also regulates intracellular levels of glutathione (GSH), an antioxidant that when elevated in cancer provides resistance against chemotherapy- and radiotherapy-induced oxidative damage. The different binding sites for drugs and GSH on MRP1 has allowed the development of small molecule MRP1 modulators that block chemotherapy efflux whilst simultaneously enhancing GSH efflux to deplete GSH. As no therapeutic options are available to combat MRP1-mediated multidrug resistance, we have been investigating MRP1 modulators for their efficacy in sensitizing MRP1-expressing cancers to treatment. MRP1 immunohistochemistry staining in ovarian and non-small cell lung cancer (NSCLC) patient samples was assessed to determine the frequency of high MRP1 expression. High MRP1 staining was frequently observed in the subcellular compartment (37%, 47%) and, to a lesser extent, plasma membrane (7%, 16%) in ovarian and NSCLC patient tumour samples respectively. In NSCLC, subcellular MRP1 was associated with poorer overall survival in late stage disease (p=0.0095) and membrane MRP1 with poorer disease-free survival in Stage 4 cancer (p=0.01449). Analysis for ovarian cancer is ongoing. As MRP1 is therefore an attractive target for inhibition, we used membrane vesicle uptake assays to compare the ability of modulators to inhibit [3H]-labelled MRP1 substrate transport. 7-(difluoromethyl)-N-4-morpholinyl-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (7914321) was identified as an analogue of the MRP1 inhibitor Reversan with improved potency. Interestingly, this inhibition was GSH dependent. Exploring further this relationship with GSH, the high MRP1-expressing A549 lung and SKOV3 ovarian cancer cell lines were treated with 7914321 alone or in combination with the GSH synthesis inhibitor buthionine sulfoximine (BSO), then GSH levels were determined by glutathione recycling assay. 7914321 stimulated GSH efflux in both cell lines in an MRP1-dependent manner and strongly synergised with BSO to cause near complete GSH depletion. To determine the potential of this synergistic GSH depletion to chemosensitize cells, the viability of A549 and SKOV3 cells treated with chemotherapy, 7914321, and BSO was assessed by clonogenic and resazurin-based cytotoxicity assays. 7914321/BSO significantly diminished clonogenicity in high but not low MRP1-expressing cells, and further sensitized cancer cell lines to MRP1-substrate chemotherapeutics compared to the single agents. Together, these findings provide preliminary evidence that 7914321 is a potent MRP1 modulator whose dual effects on MRP1 place it in a unique position to potentially enhance the therapeutic window to treat chemoresistant MRP1-overexpressing cancers. Citation Format: Kimberley M. Hanssen, Christine C. Gana, Madeleine S. Wheatley, Denise M. Yu, Claudia L. Flemming, Richard Young, Gavin M. Wright, Gwenaelle Conseil, Catherine J. Kennedy, Anna deFazio, Ben Solomon, Susan P. Cole, Murray D. Norris, Michelle Haber, Jamie I. Fletcher. Modulation of MRP1 activity reverses chemotherapy resistance in adult cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3809.
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) | 0,005 | 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 ».