The molecular pharmacology of symplostatin 1: a new antimitotic dolastatin 10 analog.
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.
Mooberry
Susan L
SL
Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA. smooberry@sfbr.org
Leal
Rachel M
RM
Tinley
Tina L
TL
Luesch
Hendrik
H
Moore
Richard E
RE
Corbett
Thomas H
TH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D047630:Depsipeptides; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007399:Interphase; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects
D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; C115534:symplostatin 1; C105791:soblidotin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C064570:dolastatin 10