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Neuroblastoma (NBL) is the most common extracranial solid tumor in children. Neuroblastomas are biologically heterogeneous and differ in their genetic characteristics. Prognostic groups are characterized by genomic changes. Approximately 40% of NBL are in the high-risk NBL group (HR-NBL), which is characterized by structural changes.(1) Improvements in the treatment of HR-NBL in the past decade have not substantially improved prognosis compared with other pediatric malignancies.(2) Chemotherapy is ultimately ineffective in curing HR-NBL because drug resistance arises in most patients, despite intensive therapy.(3,4) Recent studies have provided a link between increased metastatic potential and drug-resistant phenotypes, indicating that, in addition to the development of drug resistance, chemotherapy may cause changes in the biological characteristics of tumors.(5) Treatment of older children with disseminated NBL continues to be a considerable challenge for pediatric oncologists. The drugs used in the treatment of NBL include platinum compounds, alkylating agents, topoisomerase II (TOP2) inhibitors, anthracyclines and vincristine.(1) Recently, we suggested a novel treatment for NBL using the alkaloid ellipticine. We found that exposure of human NBL cell lines, resulted in the induction of apoptosis.(6,7) These effects were associated with the formation of covalent ellipticine-derived DNA adducts formed by cytochrome P450 (CYP)- and peroxidase-derived ellipticine metabolites. In addition to DNA adducts, the toxicity of ellipticine against NBL also involves the intercalation of DNA(8,9) and inhibition of TOP2A.(9–11) Because drug resistance is a feature of HR-NBL, the mechanisms involved in the development of resistance by NBL to anticancer drugs has been investigated.(12–14) However, there is little information available regarding the resistance to ellipticine in NBL. Previously, we determined that ellipticine was able to induce resistance in the NBL cell line UKF-NB-4; specifically, we found that ellipticine may induce resistance in UKF-NB-4 cells after long-term treatment with increasing concentrations.(6)
The aim of the present study was to investigate the mechanisms responsible for ellipticine-induced resistance in UKF-NB-4 cells. This was determined by analyzing the genetic programs in these cells. Several approaches were used, including molecular cytogenetic (comparative genomic hybridization [CGH]), multicolor (m) and interphase (i) FISH, mRNA expression detection (microarray and real-time quantitative [q] RT-PCR),...