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Título: | Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances |
Autor: | Matesanz, Ruth CSIC ; Trigili, Chiara CSIC; Rodríguez-Salarichs, Javier CSIC; Pera, Benet CSIC; Jiménez-Barbero, Jesús CSIC ORCID; Canales, Ángeles CSIC ORCID; Barasoain, Isabel CSIC ; Díaz, José Fernando CSIC ORCID | Palabras clave: | Paclitaxel Microtubules Tubulin Chemotherapy Resistance |
Fecha de publicación: | 19-jun-2014 | Editor: | Elsevier | Citación: | Bioorganic & Medicinal Chemistry (In press-Online 19 jun 2014) | Resumen: | We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by p-Gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype. We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7-S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on p-Gp and βIII overexpressing cells and on mutant cells. The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power. | Descripción: | 49 p.-7 tab.- 7 fig. | Versión del editor: | http://dx.doi.org/10.1016/j.bmc.2014.05.048 | URI: | http://hdl.handle.net/10261/100023 | DOI: | 10.1016/j.bmc.2014.05.048 | ISSN: | 0968-0896 | E-ISSN: | 1464-3391 |
Aparece en las colecciones: | (CIB) Artículos |
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Matesanz et al_2014 _Bioorganic Medicinal Chemistry.pdf | 6,75 MB | Adobe PDF | Visualizar/Abrir |
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