Mechanism of action of tubulysin, an antimitotic peptide from myxobacteria
H), By:Khalil, MW (Khalil, MW); Sasse, F (Sasse, F); Lunsdorf, H (Lunsdorf, H); Elnakady, YA (Elnakady, YA); Reichenbach, H (Reichenbach, . 2006
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 depolymerizotion 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 opporent K-i was 3 mu m. 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 dolostatin 10, phomopsin A, and hemiasterlin. Efforts are underway to develop this new group of compounds as anticancer drugs.
