Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol.
Computer-assisted structure analysis indicated (+)-discodermolide, a polyhydroxylated alkatetraene lactone marine natural product, was an antimitotic compound, and we confirmed this prediction. Previous work had shown an accumulation of discodermolide-treated cells in the G2/M portion of the cell cycle, and we have now found that discodermolide arrests Burkitt lymphoma cells in mitosis. Discodermolide-treated breast carcinoma cells displayed spectacular rearrangement of the microtubule cytoskeleton, including extensive microtubule bundling. Microtubule rearrangement that occurred with 10 nM discodermolide required 1 microM taxol. Discodermolide had equally impressive effects on tubulin assembly in vitro. Near-total polymerization occurred at 0 degree C with tubulin plus microtubule-associated proteins (MAPs) under conditions in which taxol at an identical concentration was inactive. Without MAPs and/or without GTP, tubulin assembly was also more vigorous with discodermolide than with taxol under every reaction condition examined. Discodermolide-induced polymer differed from taxol-induced polymer in that it was completely stable at 0 degree C in the presence of high concentrations of Ca2+. In a quantitative assay designed to select for agents more effective than taxol in inducing assembly, discodermolide had an EC50 value of 3.2 microM versus 23 microM for taxol.
ter Haar
E
E
Department of Environmental and Occupational Health, University of Pittsburgh, Pennsylvania 15238, USA.
Kowalski
R J
RJ
Hamel
E
E
Lin
C M
CM
Longley
R E
RE
Gunasekera
S P
SP
Rosenkranz
H S
HS
Day
B W
BW
D000473:Alkanes; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D002051:Burkitt Lymphoma; D002118:Calcium / Q000494:pharmacology; D002219:Carbamates; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000302:isolation & purification / Q000494:pharmacology*; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology*; D011161:Porifera; D011753:Pyrones; D013997:Time Factors; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D014407:Tumor Cells, Cultured
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D008869:Microtubule-Associated Proteins; D011753:Pyrones; D014404:Tubulin; D006160:Guanosine Triphosphate; C071229:discodermolide; D017239:Paclitaxel; D002118:Calcium