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Published on: March 20, 2018
Mechanisms of ellipticine-mediated resistance in UKF-NB-4 neuroblastoma cells
Pavel Procházka1, Antonín Libra, Zuzana Zemanová
1Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic.
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.
Insights
Ellipticine resistance in neuroblastoma involves multiple mechanisms, including drug efflux and altered protein expression. Understanding these pathways is crucial for developing new neuroblastoma treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High-risk neuroblastomas often develop resistance to chemotherapy, necessitating novel therapeutic agents.
- Ellipticine has demonstrated apoptosis-inducing effects in human neuroblastoma cells.
- Previous research suggested ellipticine resistance may develop with prolonged exposure.
Purpose of the Study:
- To investigate the molecular and genetic mechanisms underlying ellipticine resistance in neuroblastoma.
- To characterize the ellipticine-resistant neuroblastoma cell line UKF-NB-4(ELLI).
Main Methods:
- Comparative genomic hybridization
- Multicolor and interphase fluorescence in situ hybridization (FISH)
- Expression microarray analysis
- Real-time reverse transcription-polymerase chain reaction (RT-PCR)
- Flow cytometry
- Western blotting
Main Results:
- Ellipticine resistance is associated with Bcl-2 overexpression and topoisomerase downregulation.
- Mechanisms include drug efflux/degradation, altered DNA copy number (gains, amplifications, deletions).
- Upregulation of enzymes in oxidative phosphorylation and reduced growth rate may contribute.
Conclusions:
- Ellipticine resistance in neuroblastoma is multifactorial, involving genetic and protein-level changes.
- Identifying these resistance mechanisms is key for future drug development strategies.
- This study provides insights into overcoming therapeutic challenges in neuroblastoma treatment.
