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Page 2 of 11 Fonseka et al. J Cancer Metastasis Treat 2020;6:7 I http://dx.doi.org/10.20517/2394-4722.2019.024

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

INTRODUCTION
[1]
Neuroblastoma is the most common extracranial solid tumour that occurs in childhood . It usually
arises from the sympathetic nervous system and originates from the neuroepithelial cells of neural crest
[2]
tissues . The clinical behaviour of this complex disease is highly diverse, ranging from a benign tumour
[2,3]
mass with no symptoms to a progressive and fatal disease with resistance to current treatments . This
aggressive cancer is the most common cancer diagnosed during the first two years of human life . The
[4]
most important prognostic factor in neuroblastoma is the stage of the disease while the age of the patients
remains an independent prognostic factor. Interestingly, infants less than 12 months with stages beyond
1, have significantly better disease-free survival rates than older children who are diagnosed with the
[5-8]
same stage . The histopathologic features of tumours are also classified as favourable or unfavourable
[9]
depending on the differentiation of neuroblasts and Schwannian stroma content . In addition, the
presence of amplified transcription factor N-Myc in neuroblastoma patients (about 20%) strongly correlates
with poor prognosis and tumour dissemination. As amplification of N-Myc has a profound effect on
clinical outcome in neuroblastoma patients, N-Myc copy number has been used as a biomarker [10-12] . The
heterogeneity of neuroblastoma has resulted in decrease in the effectiveness of the therapeutic strategies
over the past decades. However, tumours with favourable prognostic markers do not require as intense
chemotherapy as the tumours with adverse factors. Hence, the Children’s Oncology Group has developed
[13]
a risk group stratification system in order to categorise the treatment strategies . This system is mainly
based on the stage of the disease, amplification status of N-Myc, DNA index and histopathology.

Even though the overall outcome of the neuroblastoma patients has improved recently, the survival rates of
the children with high-risk neuroblastoma have not shown a substantive improvement [14,15] . Hence, there is
a need for better therapeutic avenues to treat high-risk neuroblastoma [1,16,17] . Regardless of the efforts and
current developments in treating high-risk patients, most of them relapse due to acquired drug resistance.
Moreover, the survivors of high-risk neuroblastoma have manifested adverse effects to current therapeutics,
which in turn has impaired their quality of life. Some of the uncovered effects from radiotherapy
and surgery are damages to eyes, osteoporosis and various other musculoskeletal abnormalities [18,19] .
Unfortunately, damages to renal tubes, chronic abnormalities in electrolytes, impaired sexual maturation,
premature menopause and growth hormone deficiency can also occur due to long-term exposure to
chemotherapy [20-25] . When considering all these factors, there is an urgent need of developing therapeutic
strategies with natural compounds that increase the anti-cancer activity with lower side effects to enhance
the quality of life of neuroblastoma patients.

Epithelial-to-mesenchymal transition (EMT) is a cellular process where epithelial cells lose their adhesion
properties and turn mesenchymal. This highly plastic and dynamic shift towards the mesenchymal state is
considered as EMT, wherein the expression of the adhesion proteins are downregulated so as to promote
migration and invasion [26,27] . On the contrary, mesenchymal-epithelial transition (MET) is the reverse
of EMT, wherein the expression of adhesion proteins are upregulated and the cells lose the migratory
[28]
phenotype . It is well established that EMT regulates cancer metastasis. Recent evidence suggests that
EMT also regulates chemotherapeutic drug resistance in several cancer types. Human colorectal cancer
(CRC) cell lines KM12L4 and HT29 displayed EMT because of oxaliplatin resistance by translocating
β-Catenin to the nucleus . Hepatocellular carcinoma cells resistant to 5-Fluorouracil (5-FU) also showed
[29]