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

Laura D. Gamble, Stefania Purgato, Jayne Murray, Lin Xiao, Denise M.T. Yu, Kimberley M. Hanssen, Federico M. Giorgi, Daniel R. Carter, Andrew J. Gifford, Emanuele Valli, Giorgio Milazzo, Alvin Kamili, Chelsea Mayoh, Bing Liu, Georgina Eden, Sara Sarraf, Sophie Allan, Simone Di Giacomo, Claudia L. Flemming, Amanda J. Russell & 13 others Belamy B. Cheung, Andre Oberthuer, Wendy B. London, Matthias Fischer, Toby N. Trahair, Jamie I. Fletcher, Glenn M. Marshall, David S. Ziegler, Michael D. Hogarty, Mark R. Burns, Giovanni Perini, Murray D. Norris, Michelle Haber

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

LanguageEnglish
Article numberaau1099
JournalScience Translational Medicine
Volume11
Issue number477
DOIs
Publication statusPublished - 30 Jan 2019

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gamble, Laura D. ; Purgato, Stefania ; Murray, Jayne ; Xiao, Lin ; Yu, Denise M.T. ; Hanssen, Kimberley M. ; Giorgi, Federico M. ; Carter, Daniel R. ; Gifford, Andrew J. ; Valli, Emanuele ; Milazzo, Giorgio ; Kamili, Alvin ; Mayoh, Chelsea ; Liu, Bing ; Eden, Georgina ; Sarraf, Sara ; Allan, Sophie ; Giacomo, Simone Di ; Flemming, Claudia L. ; Russell, Amanda J. ; Cheung, Belamy B. ; Oberthuer, Andre ; London, Wendy B. ; Fischer, Matthias ; Trahair, Toby N. ; Fletcher, Jamie I. ; Marshall, Glenn M. ; Ziegler, David S. ; Hogarty, Michael D. ; Burns, Mark R. ; Perini, Giovanni ; Norris, Murray D. ; Haber, Michelle. / Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. In: Science Translational Medicine. 2019 ; Vol. 11, No. 477.
@article{64c304d1d5864953a5446c985cad0537,
title = "Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma",
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.",
author = "Gamble, {Laura D.} and Stefania Purgato and Jayne Murray and Lin Xiao and Yu, {Denise M.T.} and Hanssen, {Kimberley M.} and Giorgi, {Federico M.} and Carter, {Daniel R.} and Gifford, {Andrew J.} and Emanuele Valli and Giorgio Milazzo and Alvin Kamili and Chelsea Mayoh and Bing Liu and Georgina Eden and Sara Sarraf and Sophie Allan and Giacomo, {Simone Di} and Flemming, {Claudia L.} and Russell, {Amanda J.} and Cheung, {Belamy B.} and Andre Oberthuer and London, {Wendy B.} and Matthias Fischer and Trahair, {Toby N.} and Fletcher, {Jamie I.} and Marshall, {Glenn M.} and Ziegler, {David S.} and Hogarty, {Michael D.} and Burns, {Mark R.} and Giovanni Perini and Norris, {Murray D.} and Michelle Haber",
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language = "English",
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Gamble, LD, Purgato, S, Murray, J, Xiao, L, Yu, DMT, Hanssen, KM, Giorgi, FM, Carter, DR, Gifford, AJ, Valli, E, Milazzo, G, Kamili, A, Mayoh, C, Liu, B, Eden, G, Sarraf, S, Allan, S, Giacomo, SD, Flemming, CL, Russell, AJ, Cheung, BB, Oberthuer, A, London, WB, Fischer, M, Trahair, TN, Fletcher, JI, Marshall, GM, Ziegler, DS, Hogarty, MD, Burns, MR, Perini, G, Norris, MD & Haber, M 2019, 'Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma', Science Translational Medicine, vol. 11, no. 477, aau1099. https://doi.org/10.1126/scitranslmed.aau1099

Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. / Gamble, Laura D.; Purgato, Stefania; Murray, Jayne; Xiao, Lin; Yu, Denise M.T.; Hanssen, Kimberley M.; Giorgi, Federico M.; Carter, Daniel R.; Gifford, Andrew J.; Valli, Emanuele; Milazzo, Giorgio; Kamili, Alvin; Mayoh, Chelsea; Liu, Bing; Eden, Georgina; Sarraf, Sara; Allan, Sophie; Giacomo, Simone Di; Flemming, Claudia L.; Russell, Amanda J.; Cheung, Belamy B.; Oberthuer, Andre; London, Wendy B.; Fischer, Matthias; Trahair, Toby N.; Fletcher, Jamie I.; Marshall, Glenn M.; Ziegler, David S.; Hogarty, Michael D.; Burns, Mark R.; Perini, Giovanni; Norris, Murray D.; Haber, Michelle.

In: Science Translational Medicine, Vol. 11, No. 477, aau1099, 30.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma

AU - Gamble, Laura D.

AU - Purgato, Stefania

AU - Murray, Jayne

AU - Xiao, Lin

AU - Yu, Denise M.T.

AU - Hanssen, Kimberley M.

AU - Giorgi, Federico M.

AU - Carter, Daniel R.

AU - Gifford, Andrew J.

AU - Valli, Emanuele

AU - Milazzo, Giorgio

AU - Kamili, Alvin

AU - Mayoh, Chelsea

AU - Liu, Bing

AU - Eden, Georgina

AU - Sarraf, Sara

AU - Allan, Sophie

AU - Giacomo, Simone Di

AU - Flemming, Claudia L.

AU - Russell, Amanda J.

AU - Cheung, Belamy B.

AU - Oberthuer, Andre

AU - London, Wendy B.

AU - Fischer, Matthias

AU - Trahair, Toby N.

AU - Fletcher, Jamie I.

AU - Marshall, Glenn M.

AU - Ziegler, David S.

AU - Hogarty, Michael D.

AU - Burns, Mark R.

AU - Perini, Giovanni

AU - Norris, Murray D.

AU - Haber, Michelle

PY - 2019/1/30

Y1 - 2019/1/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060920448&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aau1099

DO - 10.1126/scitranslmed.aau1099

M3 - Article

VL - 11

JO - Science Translational Medicine

T2 - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 477

M1 - aau1099

ER -