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Mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole C<inf>1</inf>

Xu, FL and Rbaibi, Y and Kiselyov, K and Lazo, JS and Wipf, P and Saunders, WS (2010) Mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole C<inf>1</inf>. BMC Chemical Biology, 10.

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Abstract

Background. Disorazoles are polyene macrodiolides isolated from a myxobacterium fermentation broth. Disorazole C1was newly synthesized and found to depolymerize microtubules and cause mitotic arrest. Here we examined the cellular responses to disorazole C1in both non-cancer and cancer cells and compared our results to vinblastine and taxol. Results. In non-cancer cells, disorazole C1induced a prolonged mitotic arrest, followed by mitotic slippage, as confirmed by live cell imaging and cell cycle analysis. This mitotic slippage was associated with cyclin B degradation, but did not require p53. Four assays for apoptosis, including western blotting for poly(ADP-ribose) polymerase cleavage, microscopic analyses for cytochrome C release and annexin V staining, and gel electrophoresis examination for DNA laddering, were conducted and demonstrated little induction of apoptosis in non-cancer cells treated with disorazole C1. On the contrary, we observed an activated apoptotic pathway in cancer cells, suggesting that normal and malignant cells respond differently to disorazole C1. Conclusion. Our studies demonstrate that non-cancer cells undergo mitotic slippage in a cyclin B-dependent and p53-independent manner after prolonged mitotic arrest caused by disorazole C1. In contrast, cancer cells induce the apoptotic pathway after disorazole C1treatment, indicating a possibly significant therapeutic window for this compound. © 2010 Xu et al; licensee BioMed Central Ltd.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Xu, FL
Rbaibi, Y
Kiselyov, Kkiselyov@pitt.eduKISELYOV0000-0001-6683-2895
Lazo, JS
Wipf, Ppwipf@pitt.eduPWIPF
Saunders, WSwsaund@pitt.eduWSAUND
Date: 16 March 2010
Date Type: Publication
Journal or Publication Title: BMC Chemical Biology
Volume: 10
DOI or Unique Handle: 10.1186/1472-6769-10-1
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
Other ID: NLM PMC2834648
PubMed Central ID: PMC2834648
PubMed ID: 20181182
Date Deposited: 23 Sep 2014 15:28
Last Modified: 27 Jan 2019 06:55
URI: http://d-scholarship.pitt.edu/id/eprint/22232

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