Detail publikace

Vacuolar-ATPase-mediated intracellular sequestration of ellipticine contributes to drug resistance in neuroblastoma cells

HRABĚTA, J. GROH, T. POLJAKOVÁ, J. KHALIL, M. ADAM, V. KÍZEK, R. UHLÍK, J. DOKTOROVÁ, H. ČERNÁ, T. FREI, E. STIBOROVÁ, M. ECKSCHLAGER, T.

Originální název

Vacuolar-ATPase-mediated intracellular sequestration of ellipticine contributes to drug resistance in neuroblastoma cells

Typ

článek v časopise ve Web of Science, Jimp

Jazyk

angličtina

Originální abstrakt

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-4(ELLI) line than in the parental ellipticine-sensitive UKF-NB-4 cell line. Treatment of ellipticine-sensitive UKF-NB-4 and ellipticine-resistant UKF-NB-4(ELLI) 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-4(ELLI) 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.

Klíčová slova

neuroblastoma; resistance to ellipticine; vacuolation; drug sequestration; vacuolar ATPase

Autoři

HRABĚTA, J.; GROH, T.; POLJAKOVÁ, J.; KHALIL, M.; ADAM, V.; KÍZEK, R.; UHLÍK, J.; DOKTOROVÁ, H.; ČERNÁ, T.; FREI, E.; STIBOROVÁ, M.; ECKSCHLAGER, T.

Rok RIV

2015

Vydáno

1. 9. 2015

ISSN

1019-6439

Periodikum

INTERNATIONAL JOURNAL OF ONCOLOGY

Ročník

47

Číslo

3

Stát

Řecká republika

Strany od

971

Strany do

980

Strany počet

10

BibTex

@article{BUT123332,
  author="Jan {Hraběta} and Eva {Frei} and Marie {Stiborová} and Tomáš {Eckschlager} and Tomáš {Groh} and René {Kizek} and Jitka {Poljaková} and Mohamed Ashraf {Khalil} and Vojtěch {Adam} and Jiří {Uhlík} and Helena {Doktorová} and Tereza {Černá}",
  title="Vacuolar-ATPase-mediated intracellular sequestration of ellipticine contributes to drug resistance in neuroblastoma cells",
  journal="INTERNATIONAL JOURNAL OF ONCOLOGY",
  year="2015",
  volume="47",
  number="3",
  pages="971--980",
  doi="10.3892/ijo.2015.3066",
  issn="1019-6439"
}