Identifying a Resistance Determinant for the Antimitotic Natural Products Disorazole C1 and A1S⃞
| Autor: | Laura L. Vollmer, John S. Lazo, Eckhard Günther, Chad D. Hopkins, Carolyn A. Kitchens, Peter Wipf, Andreas Vogt, Celeste E. Reese, Thomas H. Graham |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
ATP Binding Cassette Transporter
Subfamily B Epothilone HeLa chemistry.chemical_compound Cell Line Tumor medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 RNA Small Interfering Cytotoxicity Oxazoles P-glycoprotein Cell Proliferation Pharmacology Antibiotics Antineoplastic biology biology.organism_classification Chemotherapy Antibiotics and Gene Therapy Drug Resistance Multiple Tubulin Modulators Multiple drug resistance Biochemistry chemistry Apoptosis Drug Resistance Neoplasm Epothilones biology.protein Molecular Medicine Antimitotic Agent Macrolides Growth inhibition medicine.drug |
| Popis: | 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 C1. 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. |
| Databáze: | OpenAIRE |
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