Open AccessMechanisms of ellipticine‐mediated resistance in UKF‐NB‐4 neuroblastoma cells
Author(s) -
Procházka Pavel,
Libra Antonín,
Zemanová Zuzana,
Hřebačková Jana,
Poljaková Jitka,
Hraběta Jan,
Bunček Martin,
Stiborová Marie,
Eckschlager Tomáš
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02137.x
Subject(s) - downregulation and upregulation , neuroblastoma , apoptosis , biology , topoisomerase , flow cytometry , blot , microbiology and biotechnology , microarray analysis techniques , cancer research , gene , cell culture , chemistry , gene expression , dna , biochemistry , genetics
Most high‐risk neuroblastomas develop resistance to cytostatics and therefore there is a need to develop new drugs. In previous studies, we found that ellipticine induces apoptosis in human neuroblastoma cells. We also investigated whether ellipticine was able to induce resistance in the UKF‐NB‐4 neuroblastoma line and concluded that it may be possible after long‐term treatment with increasing concentrations of ellipticine. The aim of the present study was to investigate the mechanisms responsible for ellipticine resistance. To elucidate the mechanisms involved, we used the ellipticine‐resistant subline UKF‐NB‐4 ELLI and performed comparative genomic hybridization, multicolor and interphase FISH, expression microarray, real‐time RT‐PCR, flow cytometry and western blotting analysis of proteins. On the basis of our results, it appears that ellipticine resistance in neuroblastoma is caused by a combination of overexpression of Bcl‐2, efflux or degradation of the drug and downregulation of topoisomerases. Other mechanisms, such as upregulation of enzymes involved in oxidative phosphorylation, cellular respiration, V‐ATPases, aerobic respiration or spermine synthetase, as well as reduced growth rate, may also be involved. Some changes are expressed at the DNA level, including gains, amplifications or deletions. The present study demonstrates that resistance to ellipticine is caused by a combination of mechanisms. ( Cancer Sci 2012; 103: 334–341)