FR901228 causes mitotic arrest but does not alter microtubule polymerization
V Sandor1, A R Robbins, R Robey
1Medicine Branch, National Cancer Institute, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Anti-Cancer Drugs
|September 23, 2000
Summary
FR901228, a cyclic depsipeptide, causes cancer cells to arrest in mitosis by disrupting chromosome attachment to spindles, not by affecting microtubules. This leads to prometaphase arrest and cell cycle accumulation without altering microtubule dynamics.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- FR901228 is a natural cyclic depsipeptide with high cytotoxicity against human cancer cell lines.
- Previous studies indicated a potential taxane-like mechanism for its cell cycle arrest.
- Cells treated with FR901228 arrest in G1 or G2/M phases, with S phase depletion.
Purpose of the Study:
- To elucidate the mechanism by which FR901228 induces mitotic arrest.
- To investigate whether FR901228 interferes with microtubule dynamics or chromosome attachment.
Main Methods:
- Testing FR901228 for tubulin binding and in vitro microtubule assembly.
- Examining cellular microtubules in FR901228-exposed cells.
- Analyzing cell cycle distribution and mitotic progression in various cancer cell lines (MCF7, MCF10, PC3).
Main Results:
- FR901228 did not affect tubulin binding or microtubule assembly in vitro.
- No alterations in cellular microtubules were observed after FR901228 exposure.
- FR901228 induced prometaphase arrest with unattached chromosomes and aberrant spindles, without impacting mitotic microtubules.
Conclusions:
- FR901228 induces mitotic arrest by interfering with chromosome attachment to the spindle apparatus.
- The compound causes aberrant spindle formation leading to prometaphase arrest.
- FR901228's mechanism of action differs from taxanes, as it does not directly affect microtubules.
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