title: Mechanisms of ellipticine-mediated resistance in UKF-NB-4 neuroblastoma cells.
abstract: 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.
authors: Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic.
authors: Pavel
authors: P
authors: Procházka
authors: Antonín
authors: A
authors: Libra
authors: Zuzana
authors: Z
authors: Zemanová
authors: Jana
authors: J
authors: Hřebačková
authors: Jitka
authors: J
authors: Poljaková
authors: Jan
authors: J
authors: Hraběta
authors: Martin
authors: M
authors: Bunček
authors: Marie
authors: M
authors: Stiborová
authors: Tomáš
authors: T
authors: Eckschlager
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D026942:DNA Topoisomerases / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004611:Ellipticines / Q000378:metabolism / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; D019253:Proto-Oncogene Proteins c-bcl-2; C034192:ellipticine; D026942:DNA Topoisomerases