Mechanism of Action of Tubulysin, an Antimitotic Peptide from Myxobacteria

✍ Scribed by Mohamed W. Khalil; Florenz Sasse; Heinrich Lünsdorf; Yasser A. Elnakady; Hans Reichenbach

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 317 KB
• Volume: 7
• Category: Article
• ISSN: 1439-4227
• DOI: 10.1002/cbic.200500421

✦ Synopsis

Abstract

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 G~2~/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 K~i~ was 3 μM. 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.