Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

• Published in: Oncogene Vol. 27; no. 5; pp. 694 - 699
• Main Authors: Radhakrishnan, S K, Halasi, M, Bhat, U G, Kurmasheva, R T, Houghton, P J, Gartel, A L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2008; Nature Publishing; Nature Publishing Group
• Subjects: AKT protein; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cancer; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cell cycle; Cell death; Cell growth; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Drug development; Fundamental and applied biological sciences. Psychology; Gene expression; Human Genetics; Humans; Inhibitor of Apoptosis Proteins; Internal Medicine; Mcl-1 protein; Medical sciences; Medicine; Medicine & Public Health; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - drug effects; Molecular and cellular biology; Myc protein; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - metabolism; Neuroblastoma; Neuroblastoma - pathology; Neuroblasts; Neurological disorders; Neurology; Nucleoside analogs; Nucleosides - pharmacology; Oncology; original-article; Phosphorylation; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-myc - drug effects; Proto-Oncogene Proteins c-myc - metabolism; Pyrimidines - pharmacology; Survivin; Transcription; Tumor cell lines; Tumor Cells, Cultured; Tumors of the nervous system. Phacomatoses; neuroblastoma; survivin; Mcl-1; N-myc; ARC; Akt; Nervous system diseases; Akt protein kinase; Malignant tumor; Neuroblastoma; Carcinogenesis; Autonomic neuropathy; Onc gene; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210692

We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7- β - D -ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1- β - D -ribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARC-induced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.