Abstract B016: Repurposing nelfinavir for re-sensitizing platinum-resistant high grade serous ovarian cancer cells
Notice bibliographique
Résumé
Abstract High grade serous ovarian cancer (HGSOC) is the deadliest gynecological malignancy, with a 50% 5-year survival rate. The high mortality rate of HGSOC can be partly attributed to high rates of acquired chemotherapy resistance. HGSOC is treated with surgery and platinum (Pt)-based chemotherapy, represented by cisplatin (CDDP) or CDDP derivatives. Initial treatment is often successful, however, over 80% of patients will acquire Pt resistance. Therefore, Pt resistance remains one of the greatest challenges in HGSOC therapy, and novel therapeutics that increase Pt sensitivity in resistant patients are essential. In this study, we demonstrate that the HIV protease inhibitor nelfinavir (NFV), shown in past work to have anti-cancer properties against HGSOC as a monotherapy, can re-sensitize CDDP-resistant cells to CDDP in vitro. In addition, we show that NFV and CDDP together may be sufficient to induce immunogenic cell death (ICD), an immunostimulatory form of apoptosis characterized by the release of damage associated molecular patterns (DAMPS). HGSOC cell lines that were clinically sensitive (PEO1) or resistant (PEO4) to CDDP were used in cytometric cell counting and colony formation assays to assess the toxicity of the CDDP/NFV combination. Co-treatment of CDDP at increasing concentrations together with a constant concentration of NFV reduced the IC50 of CDDP in PEO4 cells by 6-fold, back down to the IC50 of CDDP observed in PEO1 cells. Using Annexin V/7-AAD staining, we showed that CDDP and NFV together significantly increased the proportion of apoptotic PEO4 cells compared to CDDP alone. DNA damage, assessed through western blotting for gH2AX, was also significantly increased by CDDP/NFV co-treatment compared to CDDP alone. Furthermore, using flow cytometry to detect reactive oxygen species (ROS), we showed that PEO4 cells treated with NFV and CDDP showed increased ROS levels compared to either drug alone. Pre-treatment with a-tocopherol, a ROS scavenger, resulted in partial rescue of PEO4 cell viability, indicating that the toxicity is, at least in part, ROS-dependent. Through western blotting, we showed that CDDP and NFV co-treatment induces high levels of endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR). Of note, we observed increased C/EBP homologous protein (CHOP), a pro-apoptotic factor upregulated upon acute ER stress. Furthermore, co-treatment resulted in phosphorylation of eukaryotic initiation factor 2a (eIF2a), an event required for triggering ICD. Finally, through luminescence-based assays, we showed that CDDP/NFV co-treatment in PEO4 cells resulted in the extracellular release of ATP and the protein high mobility group box 1 (HMGB1), DAMPS required for the induction of ICD. Overall, our results indicate that NFV, when combined with CDDP, is capable of re-sensitizing PEO4 cells to CDDP, through increasing ROS and DNA damage ultimately resulting in apoptosis. Furthermore, NFV and CDDP trigger the ER stress response and DAMP release, suggesting the induction of ICD. Citation Format: Benjamin N. Forgie, Alicia A. Goyeneche, Carlos M. Telleria. Repurposing nelfinavir for re-sensitizing platinum-resistant high grade serous ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B016.
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) | 0,002 | 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 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 ».