2. Academic Validation
  3. Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances

Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances

  • Bioorg Med Chem. 2014 Sep 15;22(18):5078-90. doi: 10.1016/j.bmc.2014.05.048.
Ruth Matesanz 1,  Chiara Trigili 1,  Javier Rodríguez-Salarichs 2,  Ilaria Zanardi 3,  Benet Pera 1,  Aurora Nogales 4,  Wei-Shuo Fang 5,  Jesús Jímenez-Barbero 1,  Angeles Canales 1,  Isabel Barasoain 1,  Iwao Ojima 6,  J Fernando Díaz 7
Affiliations

Affiliations

  • 1 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
  • 2 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.
  • 3 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
  • 4 Instituto de Estructura de la Materia, Consejo Superior de Investigaciones Científicas IEM-CSIC, Serrano 121, 28006 Madrid, Spain.
  • 5 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.
  • 6 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.
  • 7 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: fer@cib.csic.es.
PMID: 25047938 DOI: 10.1016/j.bmc.2014.05.048
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.

Keywords

Chemotherapy; Microtubules; Paclitaxel; Resistance; Tubulin.

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