Abstract
Neuroblastoma is a childhood solid tumour originating from undifferentiated neural progenitor cells of the sympathetic nervous system. Drug resistance of childhood cancer neuroblastoma is a serious clinical problem. In the present study, we aimed to identify novel drugs that can inhibit the growth and survival of chemoresistant neuroblastoma. High-throughput screening identified a small molecule, epi-enprioline that was able to induce apoptosis of vincristine-resistant neuroblastoma cells via the mitochondrial apoptotic pathway. Epi-enprioline reduced tumour growth in multiple preclinical models, including an orthotopic neuroblastoma patient-derived xenograft model in vivo. In summary, our data suggest that epi-enprioline can be considered as a lead compound for the treatment of vincristine-resistant neuroblastoma uncovering a novel strategy, which can be further explored as a treatment for drug-resistant neuroblastoma.
Highlights
Treatment strategies for neuroblastoma (NB) patients include chemotherapy, including cyclophosphamide, cisplatin, doxorubicin, etoposide, carboplatin, and vincristine, either in combination or alone followed by surgical resection, myeloablation, and autologous stem cell rescue, radiation, and immunotherapy [1,2]
To identify a new anti-cancer drug that can affect the survival of vincristine-resistant neuroblastoma (NB) cells (VCR-20), we performed cell survival screening assay by using 10 μM of each 1360 small molecules from the National Cancer Institute (NCI)
While no differences in cell survival could be detected when cells were grown at 0.01 μM of the small molecules, a significant difference could be observed after treatment with 0.1 μM of the racemic epi-enprioline (Figure 1C)
Summary
Treatment strategies for neuroblastoma (NB) patients include chemotherapy, including cyclophosphamide, cisplatin, doxorubicin, etoposide, carboplatin, and vincristine, either in combination or alone followed by surgical resection, myeloablation, and autologous stem cell rescue, radiation, and immunotherapy [1,2]. There are numerous mechanisms involved in the development of multiple drug resistance [7,8]. These can be summarised as increased removal of drugs by transporters, enhanced drug metabolism, reduced cellular uptake, changes in the expression of drug targets, intracellular drug sequestration, and changes in the expression of genes involved in cell death, cell cycle, or DNA repair. Other processes that have been linked to drug resistance include mitochondrial alteration, autophagy, epithelial-mesenchymal transition, and cancer cell stemness. Among these mechanisms, increased expression of efflux pumps, which leads to decreased intracellular drug concentrations, is the most studied [9,10]
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