title: Didymin induces apoptosis by inhibiting N-Myc and upregulating RKIP in neuroblastoma.
abstract: 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.
authors.affiliation: Department of Diabetes and Metabolic Disease Research, National Medical Center, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.forename: Lokesh Dalasanur
authors.initials: LD
authors.lastname: Nagaprashantha
authors.forename: Rit
authors.initials: R
authors.lastname: Vatsyayan
authors.lastname: Ashutosh
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry; D006027:Glycosides / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049488:Phosphatidylethanolamine Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D005419:Flavonoids; D006027:Glycosides; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C552234:didymin