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.
Khalil
Mohamed W
MW
Department of Natural Product Biology, GBF, German Research Center for Biotechnology, 38124 Braunschweig, Germany.
Sasse
Florenz
F
Lünsdorf
Heinrich
H
Elnakady
Yasser A
YA
Reichenbach
Hans
H
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