Abstract
Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.
Highlights
Neuroblastoma (NB) is the most common extracranial solid pediatric cancer and the most frequent cancer diagnosed in the first year of life [1]
We investigated whether 4HC is cytotoxic to MYCN-amplified NB cells and we studied its mode of cell death, its effects on oxidative stress, and its effects when combined with the anticancer drugs, cisplatin and doxorubicin
We focused on studying the role of 4HC in the MYCN-amplified NB cell lines, SK-N-BE (2), and IMR-32
Summary
Neuroblastoma (NB) is the most common extracranial solid pediatric cancer and the most frequent cancer diagnosed in the first year of life [1]. The incidence of NB is 10-20 cases per million children [1, 2], yet NB is responsible for 15% of childhood deaths from cancer [3, 4]. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and poor prognosis, irrespective of patient age or disease stage [8,9,10]. In high-risk NB without MYCN amplification, there is often high Myc pathway activity, highlighting the importance of Myc as a driver of high-risk metastatic disease [13]. MYCN amplification has been associated with the lowest response rate of NB after chemotherapy [14]. Half of affected children are diagnosed with high-risk metastatic disease, and despite intensive multimodal therapy [15, 16], the overall 5-
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