Abstract 2516: ERa-targeted therapy in ovarian cancer cells by 17b-estradiol-linked chemotherapeutic hybrid; VP-128 (E2-Pt(II))
Notice bibliographique
Résumé
Abstract Since several cancers in women are estrogen-dependent due to the presence and overexpression of estrogen receptor (ER), we sought to determine the possibility to use it as a target for chemotherapy and have designed unique molecules capable of doing so. We have recently reported the synthesis of a new family of E2-platinum(II) hybrids. Earlier studies revealed VP-128 hybrid to show high efficiency compared to cisplatin towards breast cancer cells. VP-128 was also selective towards ER+ breast cancer xenografts in nude mice. In the present study, we have investigated, in vitro and in vivo, the antitumor activity of VP-128 using ovarian cancer cell (Ovcar-3, Skov-3, A2780 and A2780CP) and investigated the mode of action of this new hybrid against this type of cancer. We have also developed a new model of study by transfecting A2780 cells with ERα gene to better compare our hybrids with cells having the same genotype excepted for the presence or absence of ERα. MTT assays revealed that VP-128 decreased more efficiently the viability of ovarian cancer cells than cisplatin itself in vitro. Moreover, the expression of ERα sensitized the cells to the growth-suppressive effect of VP-128. Hoechst nuclear staining revealed an improved efficiency of VP-128 compared to cisplatin to induce apoptosis of ovarian cancer cells. Western blot analysis revealed that VP-128 induced more caspase-9, caspase-3 and PARP fragments in ovarian cancer cells compared to cisplatin, suggesting that VP-128 is more effective to kill cancer cells. VP-128 decreased the levels of XIAP and phosphorylated/active Akt more than cisplatin in ovarian cancer cells again suggesting that VP-128 has higher biological activity. The activation of caspase-independent apoptosis was observed in A2780 ER- cells, where VP-128 rapidly induced the translocation of AIF to the nucleus, as revealed by Western blot analysis of cytosolic/nuclear cell extracts and immunofluorescence microscopy. Converely, AIF subcellular localization was not modified by VP-128 in Ovcar-3 ER+ cells. Finally, using ovarian cancer cell xenografts in nude mice, we found that VP-128 had improved antitumour activity compared to cisplatin in vivo, and was more specific and selective towards hormone-dependent ER+ than ER- xenografts. Using newly A2780 ERα+ transfected cells, we observed a significant efficiency of the VP-128 hybrid to induce apoptosis compared to A2780 ERα- which further indicate specificity toward the receptor. Altogether these results highlight the therapeutic value of VP-128 for the treatment of hormone-dependent ovarian cancers, and provide preliminary proof-of-concept for efficient targeting of ERα by E2-Pt(II) linked chemotherapeutic hybrids. 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 2516. doi:10.1158/1538-7445.AM2011-2516
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 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) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 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) | 0,014 | 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 ».