Discodermolide, A Cytotoxic Marine Agent That Stabilizes Microtubules More Potently Than Taxol,
Abstract
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.
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Discodermolide is a very useful control for taxanes.
“Our cellular, in vitro and cryo-EM work has established that discodermolide, a compound that stabilizes microtubules and perturbs cell division similar to taxanes 65 , is a very useful control for taxanes.”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [65]
Discodermolide has a notably higher affinity to microtubules than paclitaxel and is a known hypernucleator of microtubules in vitro.
“Discodermolide has a notably higher affinity to microtubules than paclitaxel and is a known hypernucleator of microtubules in vitro 64,65 .”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [65]
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- Authors
- ter Haar, E., Kowalski, R. J., Hamel, E., Lin, C. M., Longley, R. E., Gunasekera, S. P., Rosenkranz, H. S., & Day, B. W.
- Affiliations
- Department of Environmental and Occupational Health, Department of Pharmaceutical Sciences, and the University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15238, Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and Division of Biomedical Marine Research, Harbor Branch Oceanographic Institution, Inc., Fort Pierce, Florida 34946
- National Institutes of Health (US)
- Corresponding author
- Day, Billy W.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1996-01-01
- Volume
- 35
- Issue
- 1
- Pages
- 243-250
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2043172025
- Cited by
- 382
- References
- 7
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 9 · 2018: 2 · 2017: 11 · 2016: 7 · 2015: 6 · 2014: 13 · 2013: 9 · 2012: 12
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- discodermolide, paclitaxel, microtubule stabilization, antimitotic agents, microtubule assembly, microtubule bundling, microtubule-associated proteins, Burkitt lymphoma cells, breast cancer cells, G2/M cell cycle arrest, marine natural products, cytotoxicity
- MeSH terms
- Alkanes, Animals, Antineoplastic Agents, Breast Neoplasms, Burkitt Lymphoma, Calcium, Carbamates, Cell Division, Cell Line, Dose-Response Relationship, Drug, Female, Guanosine Triphosphate, Humans, Kinetics, Lactones, Microscopy, Electron, Microtubule-Associated Proteins, Microtubules, Porifera, Pyrones, Time Factors, Tubulin, Tumor Cells, Cultured, Paclitaxel, Fluorescent Antibody Technique, Indirect
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