Dolastatin 11, a marine depsipeptide, arrests cells at cytokinesis and induces hyperpolymerization of purified actin.
The successful synthesis of dolastatin 11, a depsipeptide originally isolated from the mollusk Dolabella auricularia, permitted us to study its effects on cells. The compound arrested cells at cytokinesis by causing a rapid and massive rearrangement of the cellular actin filament network. In a dose-and time-dependent manner, F-actin was rearranged into aggregates, and subsequently the cells displayed dramatic cytoplasmic retraction. The effects of dolastatin 11 were most similar to those of the sponge-derived depsipeptide jasplakinolide, but dolastatin 11 was about 3-fold more cytotoxic than jasplakinolide in the cells studied. Like jasplakinolide, dolastatin 11 induced the hyperassembly of purified actin into filaments of apparently normal morphology. Dolastatin 11 was qualitatively more active than jasplakinolide and, in a quantitative assay we developed, dolastatin 11 was twice as active as jasplakinolide and 4-fold more active than phalloidin. However, in contrast to jasplakinolide and phalloidin, dolastatin 11 did not inhibit the binding of a fluorescent phalloidin derivative to actin polymer nor was it able to displace the phalloidin derivative from polymer. Thus, despite its structural similarity to other agents that induce actin assembly (all are peptides or depsipeptides), dolastatin 11 may interact with actin polymers at a distinct drug binding site.
Bai
R
R
Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland, USA.
Verdier-Pinard
P
P
Gangwar
S
S
Stessman
C C
CC
McClure
K J
KJ
Sausville
E A
EA
Pettit
G R
GR
Bates
R B
RB
Hamel
E
E
D008841:Actin Cytoskeleton / Q000187:drug effects*; D000199:Actins / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D047630:Depsipeptides; D004173:Dipodomys; D005456:Fluorescent Dyes / Q000378:metabolism; D017879:Isothiocyanates / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010590:Phalloidine / Q000494:pharmacology
D000199:Actins; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D047630:Depsipeptides; D005456:Fluorescent Dyes; D017879:Isothiocyanates; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; C097822:chondramide D; C422265:dolastatin 11; C057531:jasplakinolide; D010590:Phalloidine; C037152:isothiocyanic acid