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

Autor:	Gamble LD; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Purgato S; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy., Murray J; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Xiao L; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Yu DMT; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia., Hanssen KM; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia., Giorgi FM; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy., Carter DR; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.; School of Biomedical Engineering, University of Technology, Sydney, NSW 2007, Australia., Gifford AJ; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.; Department of Anatomical Pathology (SEALS), Prince of Wales Hospital, Randwick, NSW 2031, Australia., Valli E; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia., Milazzo G; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy., Kamili A; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia., Mayoh C; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia., Liu B; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Eden G; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Sarraf S; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Allan S; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Di Giacomo S; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy., Flemming CL; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia., Russell AJ; Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia., Cheung BB; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia., Oberthuer A; Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany., London WB; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02215, USA., Fischer M; Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany., Trahair TN; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.; Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia., Fletcher JI; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia., Marshall GM; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.; Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia., Ziegler DS; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.; Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia., Hogarty MD; Division of Oncology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA., Burns MR; Aminex Therapeutics, Aminex Therapeutics Inc., Kirkland, WA 98034, USA., Perini G; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy., Norris MD; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.; University of New South Wales Centre for Childhood Cancer Research, Sydney, NSW 2052, Australia., Haber M; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia. mhaber@ccia.unsw.edu.au.; School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2019 Jan 30; Vol. 11 (477).
DOI:	10.1126/scitranslmed.aau1099
Abstrakt:	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. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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