Neuroblastomas arise from the neural crest cells and represent the most common solid
tumors outside the nervous system in children. The amplification of N-Myc plays a primary role in the pathogenesis of
neuroblastomas, whereas acquired mutations of p53 lead to refractory and relapsed cases of
neuroblastomas. In this regard, dietary compounds which can target N-Myc and exert anticancer effects independent of p53 status acquire significance in the management of
neuroblastomas. Hence, we investigated the anticancer properties of the
flavonoid didymin in
neuroblastomas.
Didymin effectively inhibited proliferation and induced apoptosis irrespective of p53 status in
neuroblastomas.
Didymin downregulated
phosphoinositide 3-kinase, pAkt, Akt,
vimentin, and upregulated RKIP levels.
Didymin induced G(2)/M arrest along with decreasing the levels of
cyclin D1, CDK4, and
cyclin B1. Importantly,
didymin inhibited N-Myc as confirmed at
protein,
mRNA, and transcriptional level by promoter-reporter assays. High-performance liquid chromatography analysis of
didymin-treated (2 mg/kg b.w.) mice serum revealed effective oral absorption with free
didymin concentration of 2.1 μmol/L. Further in vivo mice xenograft studies revealed that
didymin-treated (2 mg/kg b.w.) animals had significant reductions in
tumors size compared with controls.
Didymin strongly inhibited the proliferation (Ki67) and angiogenesis (CD31) markers, as well as N-Myc expression, as revealed by the histopathologic examination of
paraffin-embedded section of resected
tumors. Collectively, our in vitro and in vivo studies elucidated the anticancer properties and mechanisms of action of a novel, orally active, and palatable
flavonoid didymin, which makes it a potential new approach for
neuroblastoma therapy (NANT) to target pediatric
neuroblastomas.