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.