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Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances

Ruth Matesanz1, Chiara Trigili1, Javier Rodríguez-Salarichs2

  • 1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.

Bioorganic & Medicinal Chemistry
|July 23, 2014
PubMed

Insights

New taxane compounds overcome multiple drug resistance mechanisms in cancer cells by enhancing tubulin assembly. These modified taxanes show potent activity against resistant tumors, offering a promising avenue for chemotherapy development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Taxanes are crucial chemotherapy agents, but their efficacy is limited by drug resistance.
  • Mechanisms of taxane resistance include P-glycoprotein (P-gp) overexpression, β-tubulin mutations, and βIII-tubulin isotype overexpression.
  • Novel taxane derivatives are needed to overcome these resistance mechanisms.

Purpose of the Study:

  • To investigate the activity of novel taxanes with modifications at C10 and C13 positions against various taxane-resistant cancer cell lines.
  • To characterize the interaction of these active taxanes with microtubules and their cellular effects.
  • To elucidate the biochemical and thermodynamic properties underlying their enhanced efficacy.

Main Methods:

  • Synthesis and chemical modification of taxane compounds at C10 and C13 positions.
  • In vitro testing against multiple taxane-resistant cell lines (P-gp overexpression, β-tubulin mutations, βIII-tubulin overexpression).
  • Biochemical assays (tubulin assembly induction), biophysical studies (NMR, SAXS), and cellular imaging of microtubule networks.

Main Results:

  • Four modified taxanes demonstrated significant activity against all tested resistant cell lines.
  • Enhanced potency in inducing tubulin assembly was observed compared to classical taxanes.
  • Differential interaction with the microtubule S7-S9 loop (M-loop) and altered thermodynamic properties (increased hydrophilicity) were identified.
  • Distinct effects on the cellular microtubular network, including rapid nucleation and bundling, were noted.

Conclusions:

  • Chemical modifications at C10 and C13 positions yield taxanes effective against diverse taxane resistance mechanisms.
  • Enhanced tubulin assembly induction, driven by M-loop interaction and favorable thermodynamic properties, underlies their potent activity.
  • These novel taxanes represent promising candidates for developing next-generation chemotherapy agents to combat resistant cancers.
Keywords:
ChemotherapyMicrotubulesPaclitaxelResistanceTubulin

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