Laulimalide and isolaulimalide, new paclitaxel-like microtubule-stabilizing agents.
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.
Mooberry
S L
SL
Natural Products Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu 96813, USA.
Tien
G
G
Hernandez
A H
AH
Plubrukarn
A
A
Davidson
B S
BS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology; D051381:Rats; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured