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Microtubule binding and disruption and induction of premature senescence by disorazole C <inf>1</inf>

Tierno, MB and Kitchens, CA and Petrik, B and Graham, TH and Wipf, P and Xu, FL and Saunders, WS and Raccor, BS and Balachandran, R and Day, BW and Stout, JR and Walczak, CE and Ducruet, AP and Reese, CE and Lazo, JS (2009) Microtubule binding and disruption and induction of premature senescence by disorazole C <inf>1</inf>. Journal of Pharmacology and Experimental Therapeutics, 328 (3). 715 - 722. ISSN 0022-3565

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Abstract

Disorazoles comprise a family of 29 macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Soran- gium 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 micro- tubules at interphase, misaligned chromosomes during mitosis, apoptosis, and premature senescence in the surviving cell populations. Using a tubulin polymerization assay, we found dis- orazole C 1 inhibited purified bovine tubulin polymerization, with an IC 50 of 11.8 ± 0.4 μM, and inhibited [ 3H]vinblastine binding noncompetitively, with a K i of 4.5 ± 0.6 μM. We also found noncompetitive inhibition of [ 3H]dolastatin 10 binding by disorazole C 1, with a K i of 10.6 ± 1.5 μM, 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. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tierno, MB
Kitchens, CA
Petrik, B
Graham, TH
Wipf, Ppwipf@pitt.eduPWIPF
Xu, FL
Saunders, WSwsaund@pitt.eduWSAUND
Raccor, BS
Balachandran, R
Day, BW
Stout, JR
Walczak, CE
Ducruet, AP
Reese, CE
Lazo, JS
Date: 1 March 2009
Date Type: Publication
Journal or Publication Title: Journal of Pharmacology and Experimental Therapeutics
Volume: 328
Number: 3
Page Range: 715 - 722
DOI or Unique Handle: 10.1124/jpet.108.147330
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-3565
MeSH Headings: Aging, Premature--physiopathology; Animals; Apoptosis--drug effects; Cattle; Cell Aging--drug effects; Cell Division--drug effects; Fibroblasts--cytology; Fibroblasts--drug effects; Fibroblasts--physiology; G2 Phase--drug effects; HeLa Cells--cytology; HeLa Cells--drug effects; Humans; Kinetics; Macrolides; Microtubules--drug effects; Microtubules--physiology; Myxococcales; Oxazoles--isolation & purification; Oxazoles--pharmacology; Tubulin--metabolism; Vinblastine--antagonists & inhibitors; Vinblastine--metabolism
Other ID: NLM NIHMS82129, NLM PMC2649750
PubMed Central ID: PMC2649750
PubMed ID: 19066338
Date Deposited: 25 Jun 2013 15:46
Last Modified: 19 Jun 2021 09:55
URI: http://d-scholarship.pitt.edu/id/eprint/19096

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