Abstract 3100: Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors
Notice bibliographique
Résumé
Abstract Agents targeting colchicine-binding site are recognized as valuable lead compounds in the development of new anticancer drugs. Although colchicine can effectively inhibit cell proliferation, its use as an anticancer agent has not been approved by FDA due to its inherent toxicity. To develop colchicine-binding site targeting agents with low or no toxicity, we have created and examined several chalcone derivatives, from which we have identified CTR-17 and CTR-20 as promising leads. We have examined their anti-proliferative activities using three human breast cancer cell lines (MDA-MB-468, MDA-MB-231 and MCF-7) and two matching non-cancer breast cell lines (184B5 and MCF10A). In addition, we also examined their efficacy using one leukemic cell line (K-562) and one cervical cell line (HeLa). Data from this study showed that CTR-17 and CTR-20 preferentially kill cancer cells 10-100 times over non-cancer cells. Data obtained from flow cytometry, confocal microscopy and Western blotting showed that CTR-17 and CTR-20 induced prolonged mitotic arrest prior to killing cancer cells by apoptosis. We also found that both CTR-17 and CTR-20 inhibit tubulin polymerisation and bind to purified tubulin fibers with a dissociation constant of 3.4±1.7 μM and 5.9±1.9 μM, respectively. CTR-17 competitively inhibits the binding of colchicine to tubulin with an inhibitory concentration of 8.67 μM, suggesting that CTR-17 binds to tubulin at a site close to the colchicine binding site. Molecular docking studies confirmed this binding which occurs via three hydrogen bonds and Van der Waals interactions. In our xenograft model of the human breast cancer cells, the treatment of mice with CTR-17 or CTR-20 (30 mg/kg) twice per week for 30 days effectively inhibits tumor growth. The combination of CTR compounds (15 mg/kg/week) and paclitaxel (5 mg/kg/week) increases paclitaxel's anti-tumor activity by 40-60%. Most importantly, both CTR-17 and CTR-20, when used alone or in combination with paclitaxel, showed no notable toxicity to vital organs (spleen, liver, kidney and lung). Therefore, the novel CTR-17 and CTR-20 chalcone derivatives possess substantial potential as safe and effective anticancer drugs. This project was supported in part from the funds by the Northern Ontario Heritage Funds Corporation, Northern Cancer Foundation, and The City of Greater Sudbury Development Corporation. IKL is a recipient of the Ontario Trillium Scholarship. Citation Format: Indeewari K. Lindamulage, Hai-Yen Vu, Dr. Piyush Trivedi, Dr. Hoyun Lee. Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2015-3100
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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) | 0,000 | 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) | 0,001 | 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 ».