Research ArticleNeuroblastoma

Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma

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Science Translational Medicine  30 Jan 2019:
Vol. 11, Issue 477, eaau1099
DOI: 10.1126/scitranslmed.aau1099

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A double attack on neuroblastoma

MYCN-amplified neuroblastoma (NB) is associated with an aggressive phenotype and poor outcome. Polyamine expression, critical for cell growth and survival, is increased in MYCN-amplified tumors. However, inhibition of polyamine synthesis failed in clinical trials. Now, Gamble et al. showed that, in NB cells, MYCN directly modulates polyamine synthesis, catabolism, and transport. In patient-derived cells and rodent models, MYCN directly modulated the expression of genes involved in polyamine catabolism, synthesis, and transport. Combined inhibition of polyamine synthesis and uptake increased survival in animal models of MYCN-amplified NB. These results suggest that the combined inhibition of polyamine synthesis and transport might be an effective strategy for treating MYCN-amplified NB.

Abstract

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

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