title: Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances.
abstract: 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.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Matesanz
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Chiara
authors.initials: C
authors.lastname: Trigili
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain; Centro de Estudios Avanzados de Cuba, Carretera San Antonio km 1 1/2, Valle Grande, La Lisa, Ciudad Habana CP 17100, Cuba.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Salarichs
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zanardi
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Benet
authors.initials: B
authors.lastname: Pera
authors.affiliation: Instituto de Estructura de la Materia, Consejo Superior de Investigaciones Científicas IEM-CSIC, Serrano 121, 28006 Madrid, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Nogales
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road Street, Beijing 100050, China.
authors.forename: Wei-Shuo
authors.initials: WS
authors.lastname: Fang
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Jímenez-Barbero
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Canales
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA; Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: fer@cib.csic.es.
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; D014404:Tubulin; C080625:taxane
keywords: Chemotherapy; Microtubules; Paclitaxel; Resistance; Tubulin