Laulimalide and isolaulimalide, new paclitaxel-like microtubule- stabilizing agents

Susan L. Mooberry, Georgia Tien, Anne H. Hernandez, Anuchit Plubrukarn, Bradley S. Davidson

Research output: Contribution to journalArticlepeer-review

329 Scopus citations

Abstract

A mechanism-based screening program aimed at the discovery of new antimicrotubule agents from natural products yielded laulimalide and isolaulimalide, two compounds with paclitaxel-like microtubule-stabilizing activity. Treatment of A-10 cells with laulimalide resulted in a dose- dependent reorganization of the cellular microtubule network and the formation of microtubule bundles and abnormal mitotic spindles. Coincident with the microtubule changes, these two compounds induced nuclear convolution and the formation of multiple micronuclei. Laulimalide is a potent inhibitor of cellular proliferation with IC50 values in the low nanomolar range, whereas isolaulimalide is much less potent with IC50 values in the low micromolar range. In contrast to paclitaxel, both laulimalide and isolaulimalide inhibited the proliferation of SKVLB-1 cells, a P-glycoprotein overexpressing multidrug-resistant cell line, suggesting that they are poor substrates for transport by P-glycoprotein. Incubation of MDA-MB-435 cells with laulimalide resulted in mitotic arrest and activation of the caspase cascade of proteolytic enzymes that accompany apoptotic cell death. Laulimalide stimulated tubulin polymerization and, although less potent than paclitaxel, it was more effective. Laulimalide-induced tubulin polymers resembled paclitaxel-induced polymers, although the laulimalide-induced polymers appeared notably longer. Laulimalide and isolaulimalide represent a new class of microtubule-stabilizing agents with activities that may provide therapeutic utility.

Original languageEnglish (US)
Pages (from-to)653-660
Number of pages8
JournalCancer Research
Volume59
Issue number3
StatePublished - Feb 1 1999
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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