Combinatorial treatment of curcumin or silibinin with doxorubicin sensitises high-risk neuroblastoma

Abstract

Aim: Neuroblastoma is a pediatric cancer of the sympathetic nervous system. Using various parameters including stage of the disease, amplification status of N-Myc, DNA index and histopathology, neuroblastoma can be stratified into low- and high-risk groups. Recent advances in treatment have significantly improved the survival rate of low-risk neuroblastoma patients. However, the overall survival rate of high-risk neuroblastoma group, especially N-Myc amplified patients, is poor. Moreover, the survivors of both low- and high-risk neuroblastoma manifest adverse side effects to chemotherapy and thus their quality of life is impaired. Considering all these factors, there is an urgent need to develop therapeutic strategies with natural compounds to improve the survival rate and to reduce the side effects. In this study, we hypothesised that the mesenchymal nature of neuroblastoma cells is a reason, at least in part, for the aggressive and treatment resistant phenotype.

Methods: In order to validate our hypothesis, we used publicaly available RNA-Seq data, in vitro assays and xenograft mouse models.

Results: Using a combinatorial treatment of mesenchymal-to-epithelial inducers (curcumin or silibinin) with doxorubicin significantly increased the cell death in a panel of neuroblastoma cells in vitro. Follow up analysis in vivo, confirmed the therapeutic benefit of utilising the combination of curcumin with doxorubicin. The combinatorial therapy significantly reduced the tumor burden and increased the survival of mice implanted with high-risk neuroblastoma cells.

Conclusion: Taken together, this study shows the efficacy of using curcumin in combination with doxorubicin to improve the survival rate and has the potential to enhance the quality of life of neuroblastoma patients.

Keywords

Neuroblastoma / epithelial-to-mesenchymal transition / curcumin / silibinin / combinatorial therapy

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