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Differential effects of natural product microtubule stabilizers on microtubule assembly: single agent and combination studies with taxol, epothilone B, and discodermolide.

Authors
  • Gertsch, Jürg1
  • Meier, Sarah
  • Müller, Martin
  • Altmann, Karl-Heinz
  • 1 Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Wolfgang-Pauli-Strasse 10, Zürich, Switzerland. , (Switzerland)
Type
Published Article
Journal
ChemBioChem
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jan 05, 2009
Volume
10
Issue
1
Pages
166–175
Identifiers
DOI: 10.1002/cbic.200800556
PMID: 19058273
Source
Medline
License
Unknown

Abstract

A systematic comparison has been performed of the morphology and stability of microtubules (MTs) induced by the potent microtubule-stabilizing agents (MSAs) taxol, epothilone B (Epo B), and discodermolide (DDM) under GTP-free conditions. DDM-induced tubulin polymerization occurred significantly faster than that induced by taxol and Epo B. At the same time, tubulin polymers assembled from soluble tubulin by DDM were morphologically distinct (shorter and less ordered) from those induced by either taxol or Epo B, as demonstrated by electron microscopy. Exposure of MSA-induced tubulin polymers to ultrasound revealed the DDM-based polymers to be less stable to this type of physical stress than those formed with either Epo B or taxol. Interestingly, MT assembly in the presence of both DDM and taxol appeared to produce a distinct new type of MT polymer with a mixed morphology between those of DDM- and taxol-induced structures. The observed differences in MT morphology and stability might be related, at least partly, to differences in intramicrotubular tubulin isotype distribution, as DDM showed a different pattern of beta-tubulin isotype usage in the assembly process.

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