Differential effects of natural product microtubule stabilizers on microtubule assembly: single agent and combination studies with taxol, epothilone B, and discodermolide.
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.
Gertsch
Jürg
J
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.
Meier
Sarah
S
Müller
Martin
M
Altmann
Karl-Heinz
KH
D000473:Alkanes / Q000494:pharmacology*; D000818:Animals; D001688:Biological Products / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002219:Carbamates / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D034261:Epothilones / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D009391:Nephelometry and Turbidimetry; D017239:Paclitaxel / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011753:Pyrones / Q000494:pharmacology*; D013552:Swine; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
D000473:Alkanes; D001688:Biological Products; D002219:Carbamates; D004338:Drug Combinations; D034261:Epothilones; D007783:Lactones; D011753:Pyrones; D014404:Tubulin; D050257:Tubulin Modulators; C071229:discodermolide; D017239:Paclitaxel; C093788:epothilone B