Abstract |
Peloruside A (PelA), a novel microtubule- stabilizing agent and potential anti- cancer drug, isolated from the marine sponge Mycale hentscheli, binds to a distinct, non- taxoid binding site on tubulin. Using live-cell confocal microscopy, the effects of PelA on microtubule dynamics were quantified in a human breast adenocarcinoma cell line (MCF7) stably expressing GFP-α- tubulin. Changes in microtubule length were tracked over time in cells treated with PelA concentrations ranging from 3.8-100 nM. As with other microtubule-targeting drugs like paclitaxel and epothilone B, microtubule dynamics were suppressed in a concentration-dependent manner. At the PelA IC₅₀ concentrations for cell proliferation (3.8 nM) and G₂/M block (25 nM), PelA inhibited dynamicity by 23% and 45%, respectively. At 25 nM PelA, effects included a 24% and 41% reduction in average growth rate and growth length, respectively. Additionally, the total time spent in pause increased by 53% and coincided with a 36% reduction in the average amount of time spent growing. Rescue and catastrophe frequencies were not significantly affected by PelA, except for length-based catastrophe (67% increase). The results provide further insight into PelA's unique mode of stabilization and contribute to our understanding of how microtubule-targeting agents exert their anti-mitotic effects.
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Authors | Ariane Chan, Peter M Andreae, Peter T Northcote, John H Miller |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 29
Issue 4
Pg. 615-26
(Aug 2011)
ISSN: 1573-0646 [Electronic] United States |
PMID | 20169398
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Bridged Bicyclo Compounds, Heterocyclic
- Epothilones
- Lactones
- peloruside A
- epothilone B
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Topics |
- Breast Neoplasms
(metabolism)
- Bridged Bicyclo Compounds, Heterocyclic
(chemistry, pharmacology)
- Cell Line, Tumor
- Epothilones
(pharmacology)
- Female
- Humans
- Lactones
(chemistry, pharmacology)
- Microtubules
(drug effects, metabolism)
- Time Factors
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