NDLI: Microtubule binding and disruption and induction of premature senescence by disorazole C(1).

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Tierno, Marni Brisson Kitchens, Carolyn A. Petrik, Bethany Graham, Thomas H. Wipf, Peter Xu, Fengfeng L. Saunders, William S. Raccor, Brianne S. Balachandran, Raghavan Day, Billy W. Stout, Jane R. Walczak, Claire E. Ducruet, Alexander P. Reese, Celeste E. Lazo, John S.
Description	Country affiliation: United States Author Affiliation: Tierno MB ( Department of Pharmacology and Chemical Biology, University of Pittsburgh Drug Discovery Institute, Biomedical Science Tower 3, Suite 10040, 3401 Fifth Avenue, University of Pittsburgh, Pittsburgh, PA 15260, USA.)
Abstract	Disorazoles comprise a family of 29 macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. The major fermentation product, disorazole A(1), was found previously to irreversibly bind to tubulin and to have potent cytotoxic activity against tumor cells, possibly because of its highly electrophilic epoxide moiety. To test this hypothesis, we synthesized the epoxide-free disorazole C(1) and found it retained potent antiproliferative activity against tumor cells, causing prominent G(2)/M phase arrest and inhibition of in vitro tubulin polymerization. Furthermore, disorazole C(1) produced disorganized microtubules at interphase, misaligned chromosomes during mitosis, apoptosis, and premature senescence in the surviving cell populations. Using a tubulin polymerization assay, we found disorazole C(1) inhibited purified bovine tubulin polymerization, with an IC(50) of 11.8 +/- 0.4 microM, and inhibited [3H]vinblastine binding noncompetitively, with a K(i) of 4.5 +/- 0.6 microM. We also found noncompetitive inhibition of [3H]dolastatin 10 binding by disorazole C(1), with a K(i) of 10.6 +/- 1.5 microM, indicating that disorazole C(1) bound tubulin uniquely among known antimitotic agents. Disorazole C(1) could be a valuable chemical probe for studying the process of mitotic spindle disruption and its relationship to premature senescence.
File Format	HTM / HTML
ISSN	00223565
e-ISSN	15210103
DOI	10.1124/jpet.108.147330
Journal	Journal of Pharmacology and Experimental Therapeutics
Issue Number	3
Volume Number	328
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2009-03-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Cytology Cell Aging Discipline Pharmacology Antagonists & Inhibitors Tubulin Oxazoles Cell Division Fibroblasts G2 Phase Physiology Vinblastine Macrolides Isolation & Purification Pharmacology Aging, Premature Metabolism Drug Effects Physiopathology Myxococcales Animals Discipline Therapeutics Microtubules Kinetics Hela Cells Apoptosis
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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Microtubule Binding and Disruption and Induction of Premature Senescence by Disorazole C1 S⃞

The microtubule cytoskeleton is required for a G2 cell cycle delay in cancer cells lacking stathmin and p53.

Megakaryocyte lineage-specific class VI ß-tubulin suppresses microtubule dynamics, fragments microtubules, and blocks cell division.

Identifying a resistance determinant for the antimitotic natural products disorazole C1 and A1.

Effect of tau on the vinblastine-induced aggregation of tubulin

Quantitative analysis of tubulin and microtubule compartments in isolated rat hepatocytes

Epigallocatechin-3-gallate shows anti-proliferative activity in HeLa cells targeting tubulin-microtubule equilibrium.

End-binding proteins sensitize microtubules to the action of microtubule-targeting agents.

Regulation of microtubule dynamics and nucleation during polarization in MDCK II cells

Microtubule binding and disruption and induction of premature senescence by disorazole C(1).

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Microtubule Binding and Disruption and Induction of Premature Senescence by Disorazole C1 S⃞

The microtubule cytoskeleton is required for a G2 cell cycle delay in cancer cells lacking stathmin and p53.

Megakaryocyte lineage-specific class VI ß-tubulin suppresses microtubule dynamics, fragments microtubules, and blocks cell division.

Identifying a resistance determinant for the antimitotic natural products disorazole C1 and A1.

Effect of tau on the vinblastine-induced aggregation of tubulin

Quantitative analysis of tubulin and microtubule compartments in isolated rat hepatocytes

Epigallocatechin-3-gallate shows anti-proliferative activity in HeLa cells targeting tubulin-microtubule equilibrium.

End-binding proteins sensitize microtubules to the action of microtubule-targeting agents.

Regulation of microtubule dynamics and nucleation during polarization in MDCK II cells

Microtubule binding and disruption and induction of premature senescence by disorazole C(1).