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: Pavel Procházka, Antonín Libra, Zuzana Zemanová, Jana Hřebačková, Jitka Poljaková, Jan Hraběta, Martin Bunček, Marie Stiborová, Tomáš Eckschlager
• Journal: Cancer science (Cancer Sci) Vol. 103 Issue 2 Pg. 334-41 (Feb 2012) ISSN: 1349-7006 [Electronic] England
• PMID: 22040216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Ellipticines
• Proto-Oncogene Proteins c-bcl-2
• ellipticine
• DNA Topoisomerases

Topics

• Antineoplastic Agents (metabolism, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Comparative Genomic Hybridization
• DNA Topoisomerases (biosynthesis)
• Drug Resistance, Neoplasm (genetics)
• Ellipticines (metabolism, pharmacology)
• Flow Cytometry
• Humans
• In Situ Hybridization, Fluorescence
• Neuroblastoma (drug therapy, genetics, metabolism, pathology)
• Oligonucleotide Array Sequence Analysis
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction