12584751

pubmed:Citation

4

Symplostatin 1, an analog of dolastatin 10, was recently isolated from cyanobacteria of the genus Symploca. Symplostatin 1 is a potent inhibitor of cell proliferation with IC(50) values in the low nanomolar range and it exhibits efficacy against a variety of cancer cell types. Symplostatin 1 caused the formation of abnormal mitotic spindles and accumulation of cells in metaphase at concentrations that had only minor effects on interphase microtubules. At higher concentrations, symplostatin 1 caused the loss of interphase microtubules. Cell cycle analysis revealed that symplostatin 1 caused G(2)/M arrest, consistent with its effects on mitotic spindles. Symplostatin 1 initiated the phosphorylation of Bcl-2, formation of micronuclei and activation of caspase 3, indicating induction of apoptosis. The cellular effects of symplostatin 1 are consistent with other antimitotic tubulin-targeting drugs. Tubulin polymerization experiments indicated that symplostatin 1 potently inhibits the assembly of purified tubulin, suggesting that tubulin may be its intracellular target. Some microtubule-targeting agents are reported to have antiangiogenic activity and therefore the effects of symplostatin 1 on endothelial cell proliferation and invasion were evaluated. Symplostatin 1 was found to be a potent inhibitor of both endothelial cell proliferation and invasion. Because of its potent and broad activity in vitro, symplostatin 1 was evaluated in vivo. Symplostatin 1 was active against murine colon 38 and murine mammary 16/C; however, it was poorly tolerated and the mice were slow to recover from the toxicity. The data indicate that symplostatin 1 has a mechanism of action similar to dolastatin 10.

eng

IM

MEDLINE

0020-7136

Copyright 2003 Wiley-Liss, Inc.

20

NLM

512-21

pubmed-meshheading:12584751-Animals, pubmed-meshheading:12584751-Antineoplastic Agents, pubmed-meshheading:12584751-Caspase 3, pubmed-meshheading:12584751-Caspases, pubmed-meshheading:12584751-Cell Nucleus, pubmed-meshheading:12584751-Cells, Cultured, pubmed-meshheading:12584751-Depsipeptides, pubmed-meshheading:12584751-Drug Resistance, Multiple, pubmed-meshheading:12584751-Drug Resistance, Neoplasm, pubmed-meshheading:12584751-Endothelium, Vascular, pubmed-meshheading:12584751-Humans, pubmed-meshheading:12584751-Interphase, pubmed-meshheading:12584751-Mice, pubmed-meshheading:12584751-Mice, Inbred C57BL, pubmed-meshheading:12584751-Microtubules, pubmed-meshheading:12584751-Mitosis, pubmed-meshheading:12584751-Mitotic Spindle Apparatus, pubmed-meshheading:12584751-Neoplasms, Experimental, pubmed-meshheading:12584751-Oligopeptides, pubmed-meshheading:12584751-Phosphorylation, pubmed-meshheading:12584751-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:12584751-Rats, pubmed-meshheading:12584751-Tubulin

The molecular pharmacology of symplostatin 1: a new antimitotic dolastatin 10 analog.

Journal Article, Research Support, U.S. Gov't, P.H.S.