Mechanism of action of tubulysin, an antimitotic peptide from myxobacteria.
Tubulysin A is a highly cytotoxic peptide with antimitotic activity that induces depletion of cell microtubules and triggers the apoptotic process. Treated cells accumulated in the G2/M phase. Tubulysin A inhibited tubulin polymerization more efficiently than vinblastine and induced depolymerization of isolated microtubule preparations. Microtubule depolymerization could not be prevented by preincubation with epothilone B and paclitaxel, neither in cell-free systems nor in cell lines. In competition experiments, tubulysin A strongly interfered with the binding of vinblastine to tubulin in a noncompetitive way; the apparent Ki was 3 microM. Electron microscopy investigations showed that tubulysin A induced the formation of rings, double rings, and pinwheel structures. The mode of action of tubulysin A resembled that of peptide antimitotics dolastatin 10, phomopsin A, and hemiasterlin. Efforts are underway to develop this new group of compounds as anticancer drugs.
Department of Natural Product Biology, GBF, German Research Center for Biotechnology, 38124 Braunschweig, Germany.
Mohamed W
MW
Khalil
Florenz
F
Sasse
Heinrich
H
Lünsdorf
Yasser A
YA
Elnakady
Hans
H
Reichenbach
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008854:Microscopy, Electron; D008968:Molecular Conformation; D009231:Myxococcales / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013997:Time Factors
D000970:Antineoplastic Agents; D009842:Oligopeptides; C510756:tubulysin A