Abstract 4339: Evaluation of polyamine inhibitors in N/S/I-type neuroblastoma and hypoxia

Abstract

Abstract Background: Neuroblastoma (NB) is the most common extracranial childhood tumor and is derived from neural crest cells of the sympathetic nervous system. There is currently no curative treatment for children with relapsed/refractory NB, and for these children the 5-year survival rate is <10%. As such, new therapeutic approaches with alternative modes of action are needed for treatment. Since MYCN controls a number of genes including ornithine decarboxylase (ODC), we proposed that ODC should be considered as a novel target for MYC-driven tumors such as NB (Oncogene, 2005, 24:5606-18; Int J Cancer, 2010, 126:2012-24). Our previous research identified two polyamine inhibitors, DFMO and SAM486A, as effective agents for the treatment of NB (Cancer Res, 2008, 68:9825-31; Mol Cancer Ther, 2009, 8:2067-75). Methods: We utilized in vitro MTS cell viability testing to assess the differential effects of DFMO and SAM486A in three specific NB cell sub-populations (neuroblastic (N), Schwann cell-like/adherent (S), and an intermediate (I) morphology types) in the presence or absence of functional tumor suppressor p53. A hypoxia chamber, Western blot analysis, and microscopy were applied to analyze the effect of polyamine inhibitors in a hypoxic environment. Results: While weak apoptosis was induced by DFMO in all three cell types with non-functional p53, SAM486A was most potent in N-type NB cells with functional p53. Interestingly, the potency of SAM486A in p53 wt cells under hypoxic conditions was significantly reduced. Conclusion: Our data provide evidence that the p53 status, NB cell sub-type and the presence/absence of oxygen in the tumor cell environment are crucial factors and determine the overall sensitivity of individual polyamine inhibitors. These new insights are important as polyamine metabolism-targeted NB therapy with DFMO has now entered the clinical stage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4339. doi:10.1158/1538-7445.AM2011-4339