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

Susan L. Mooberry, Rachel M. Leal, Tina L. Tinley, Hendrik Luesch, Richard E. Moore, Thomas H. Corbett

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Symplostatin I, an analog of dolastatin 10, was recently isolated from cyanobacteria of the genus Symploca. Symplostatin I is a potent inhibitor of cell proliferation with IC50 values in the low nanomolar range and it exhibits efficacy against a variety of cancer cell types. Symplostatin I 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 I caused the loss of interphase microtubules. Cell cycle analysis revealed that symplostatin I caused G2/M arrest, consistent with its effects on mitotic spindles. Symplostatin I initiated the phosphorylation of Bcl-2, formation of micronuclei and activation of caspase 3, indicating induction of apoptosis. The cellular effects of symplostatin I are consistent with other antimitotic tubulin-targeting drugs. Tubulin polymerization experiments indicated that symplostatin I 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 I on endothelial cell proliferation and invasion were evaluated. Symplostatin I was found to be a potent inhibitor of both endothelial cell proliferation and invasion. Because of its potent and broad activity in vitro, symplostatin I was evaluated in vivo. Symplostatin I 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 I has a mechanism of action similar to dolastatin 10.

Original languageEnglish (US)
Pages (from-to)512-521
Number of pages10
JournalInternational Journal of Cancer
Volume104
Issue number4
DOIs
StatePublished - Apr 20 2003

Keywords

  • Drug discovery
  • Microtubules
  • Natural products
  • Tubulin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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