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Identifying a resistance determinant for the antimitotic natural products disorazole C<inf>1</inf> and A<inf>1</inf>

Lazo, JS and Reese, CE and Vogt, A and Vollmer, LL and Kitchens, CA and Günther, E and Graham, TH and Hopkins, CD and Wipf, P (2010) Identifying a resistance determinant for the antimitotic natural products disorazole C<inf>1</inf> and A<inf>1</inf>. Journal of Pharmacology and Experimental Therapeutics, 332 (3). 906 - 911. ISSN 0022-3565

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Abstract

Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A1 and its much rarer companion disorazole C1 exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, promoting apoptosis or premature senescence. It is uncertain what conveys tumor cell sensitivity to these complex natural products. Therefore, we generated and characterized human tumor cells resistant to disorazole C1. Resistant cells proved exceedingly difficult to generate and required single step mutagenesis with chronic stepwise exposure to increasing concentrations of disorazole C1. Compared with wild-type HeLa cells, disorazole C1-resistant HeLa/DZR cells were 34- and 8-fold resistant to disorazole C1 and disorazole A1 growth inhibition, respectively. HeLa/DZR cells were also remarkably cross-resistant to vinblastine (280-fold), paclitaxel (2400-fold), and doxorubicin (47-fold) but not cisplatin, suggesting a multidrug-resistant phenotype. Supporting this hypothesis, MCF7/MDR cells were 10-fold cross-resistant to disorazole C 1. HeLa/DZR disorazole resistance was not durable in the absence of chronic compound exposure. Verapamil reversed HeLa/DZR resistance to disorazole C1 and disorazole A1. Moreover, HeLa/DZR cells expressed elevated levels of the drug resistance ATP-binding cassette ABCB1 transporter. Loss of ABCB1 by incubation with short interfering RNA restored sensitivity to the disorazoles. Thus, the multidrug resistance transporter ABCB1 can affect the cytotoxicity of both disorazole C1 and A1. Disorazole C1, however, retained activity against cells resistant against the clinically used microtubule-stabilizing agent epothilone B. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lazo, JSlazo@pitt.eduLAZO
Reese, CE
Vogt, A
Vollmer, LL
Kitchens, CA
Günther, E
Graham, TH
Hopkins, CD
Wipf, Ppwipf@pitt.eduPWIPF
Date: 1 March 2010
Date Type: Publication
Journal or Publication Title: Journal of Pharmacology and Experimental Therapeutics
Volume: 332
Number: 3
Page Range: 906 - 911
DOI or Unique Handle: 10.1124/jpet.109.162842
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-3565
MeSH Headings: Antibiotics, Antineoplastic--pharmacology; Cell Line, Tumor; Cell Proliferation--drug effects; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones--pharmacology; Humans; Macrolides--pharmacology; Oxazoles--pharmacology; P-Glycoprotein--biosynthesis; P-Glycoprotein--genetics; RNA, Small Interfering--genetics; Tubulin Modulators--pharmacology
Other ID: NLM PMC2835430
PubMed Central ID: PMC2835430
PubMed ID: 20008956
Date Deposited: 07 Jun 2013 20:47
Last Modified: 22 Jun 2021 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/18826

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