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. (Cancer Sci 2012; 103: 334-341)

A Novel Anticancer Agent, 8-Methoxypyrimido[4′,5′:4,5]thieno(2,3-b) Quinoline-4(3H)-One Induces Neuro 2a Neuroblastoma Cell Death through p53-Dependent, Caspase-Dependent and -Independent Apoptotic Pathways

“…Ellipticine has been successfully used to treat various types of cancer such as acute myeloblastic leukemia, osteolytic breast cancer metastasis, kidney cancers, brain tumours [11] and neuroblastoma [12], [13], [14] with limited toxic side effects and complete lack of haematological toxicity [15]. However, ellipticine resistant neuroblastoma cells have also been reported [16]. Since, high-risk neuroblastomas develop resistance to cytostatics; development of new drugs to handle these solid tumours is a constant need.…”

Ellipticine-loaded apoferritin nanocarrier retains DNA adduct-based cytochrome P450-facilitated toxicity in neuroblastoma cells

“…For instance, the clinical application of ellipticine is greatly limited by hydrophobicity and severe adverse toxic effects, including nephrotoxicity, hemolysis, xerostomia, hypertension, nausea and vomiting (Garbett and Graves, 2004;Stiborová et al, 2011;Stiborova and Frei, 2014). To some extent, the development of chemoresistance has been observed (Poljaková et al, 2009;Procházka et al, 2012;Hrabeta et al, 2015). One approach in mitigating these adverse effects is the encapsulation of ellipticine inside suitable nanocarrier, allowing targeted delivery to the tumor tissue while avoiding healthy cells (Chomoucka et al, 2010;Petros and DeSimone, 2010;Ali et al, 2011;Ryvolova Svenson, 2012;2013;Dostalova et al, 2016).…”

Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

“…UKF-NB-3 and UKF-NB-4 cell lines with MYCN amplification were established from bone marrow metastases of two patients with HR NBL. The UKF-NB-4 cell line that was established from recurrent disease already possessed the intrinsic multidrug resistance phenotype including 7q21 gain (21 Subsequent CDDP treatment. The above characterized cells were exposed to 100, 1,000, 2,000 and 3,000 ng/ml CDDP 24 h after seeding.…”

“…The above-mentioned results reporting equal or increased MYCN expression in CDDP-resistant cell seem to differ from our findings. An explanation may be that the induction of multiple changes in the genome of resistant cells indicates that cytostatics induce drug-resistance through multiple mechanisms (21,39). It is possible that NBL cells without amplification of the MYCN used in the above mentioned study (38) have normally functioning apoptotic pathways, but in relation to drug-resistance, there is a defect in one of these pathways, possibly due to increased MYCN expression.…”