Dolastatin 11, a marine depsipeptide, arrests cells at cytokinesis and induces hyperpolymerization of purified actin

The successful synthesis of dolastatin 11, a depsipeptide originally isolat ed from the mollusk Dolabella auricularia, permitted us to study its effect s on cells. The compound arrested cells at cytokinesis by causing a rapid a nd massive rearrangement of the cellular actin filament network. In a dose- and time- dependent manner, F-actin was rearranged into aggregates, and su bsequently the cells displayed dramatic cytoplasmic retraction. The effects of dolastatin 11 were most similar to those of the sponge-derived depsipep tide jasplakinolide, but dolastatin 11 was about 3-fold more cytotoxic than jasplakinolide in the cells studied. Like jasplakinolide, dolastatin 11 in duced the hyperassembly of purified actin into filaments of apparently norm al morphology. Dolastatin 11 was qualitatively more active than jasplakinol ide and, in a quantitative assay we developed, dolastatin 11 was twice as a ctive as jasplakinolide and 4-fold more active than phalloidin. However, in contrast to jasplakinolide and phalloidin, dolastatin 11 did not inhibit t he binding of a fluorescent phalloidin derivative to actin polymer nor was it able to displace the phalloidin derivative from polymer. Thus, despite i ts structural similarity to other agents that induce actin assembly (all ar e peptides or depsipeptides), dolastatin 11 may interact with actin polymer s at a distinct drug binding site.