Vacuolar-ATPase-mediated intracellular sequestration of ellipticine contributes to drug resistance in neuroblastoma cells
Language English Country Greece Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26134421
DOI
10.3892/ijo.2015.3066
Knihovny.cz E-resources
- MeSH
- DNA Adducts metabolism MeSH
- Antineoplastic Agents pharmacokinetics pharmacology MeSH
- Apoptosis MeSH
- Drug Resistance, Neoplasm * drug effects MeSH
- Chloroquine pharmacology MeSH
- Ellipticines pharmacokinetics pharmacology MeSH
- Humans MeSH
- Macrolides pharmacology MeSH
- Cell Line, Tumor MeSH
- Neuroblastoma drug therapy genetics metabolism MeSH
- Vacuolar Proton-Translocating ATPases metabolism MeSH
- Vacuoles metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Antineoplastic Agents MeSH
- bafilomycin A MeSH Browser
- Chloroquine MeSH
- Ellipticines MeSH
- ellipticine MeSH Browser
- Macrolides MeSH
- Vacuolar Proton-Translocating ATPases MeSH
Neuroblastoma is the most common cancer in infants and the fourth most common cancer in children. Aggressive cell growth and chemoresistance are notorious obstacles in neuroblastoma therapy. Exposure to the anticancer drug ellipticine inhibits efficiently growth of neuroblastoma cells and induces apoptosis in these cells. However, ellipticine induced resistance in these cells. The upregulation of a vacuolar (V)-ATPase gene is one of the factors associated with resistance development. In accordance with this finding, we found that levels of V-ATPase protein expression are higher in the ellipticine-resistant UKF-NB-4ELLI line than in the parental ellipticine-sensitive UKF-NB-4 cell line. Treatment of ellipticine-sensitive UKF-NB-4 and ellipticine-resistant UKF-NB-4ELLI cells with ellipticine-induced cytoplasmic vacuolization and ellipticine is concentrated in these vacuoles. Confocal microscopy and staining of the cells with a lysosomal marker suggested these vacuoles as lysosomes. Transmission electron microscopy and no effect of an autophagy inhibitor wortmannin ruled out autophagy. Pretreatment with a V-ATPase inhibitor bafilomycin A and/or the lysosomotropic drug chloroquine prior to ellipticine enhanced the ellipticine‑mediated apoptosis and decreased ellipticine-resistance in UKF-NB-4ELLI cells. Moreover, pretreatment with these inhibitors increased formation of ellipticine-derived DNA adducts, one of the most important DNA-damaging mechanisms responsible for ellipticine cytotoxicity. In conclusion, resistance to ellipticine in the tested neuroblastoma cells is associated with V-ATPase-mediated vacuolar trapping of this drug, which may be decreased by bafilomycin A and/or chloroquine.
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