Abstract
Despite significant improvement of neuroblastoma (NB) patients’ survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB’s susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.
Highlights
Neuroblastoma (NB) is a pediatric cancer that arises from neural crest progenitor cells of the developing sympathetic nervous system
We analyzed, in the same sections, the presence of apoptotic cells, by TUNEL assay. We found that both fendiline concentrations co-administered with cisplatin led to a significant increase in the percentage of apoptotic cells (p < 0.01) with respect to control group; the combination treatment with
We observed a statistically significant decrease of GD2+ cells in NB nodules treated with the combo-therapy with both fendiline doses (3 mg/kg: p < 0.05; 5 mg/kg: p < 0.01), as compared to those treated with cisplatin alone
Summary
Neuroblastoma (NB) is a pediatric cancer that arises from neural crest progenitor cells of the developing sympathetic nervous system. NB is the second most common solid tumor of childhood and typically affects children before school age, in some cases it may occur in young adolescents and adults [4,5,6]. Current chemotherapeutic treatments expose NB patients to high acute life-threatening toxicities, and cancer survivors have a significantly high risk to develop severe disabling chronic illnesses. In this context, the development of novel therapeutic approaches that combine high efficacy with low toxicity are urgently needed [1,2,3,4,5,6,7]
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