Synergistic drug combination GC7/DFMO suppresses hypusine/spermidine-dependent eIF5A activation and induces apoptotic cell death in neuroblastoma

The Biochemical Journal
Chad R SchultzAndré S Bachmann

Abstract

The eukaryotic initiation factor 5A (eIF5A), which contributes to several crucial processes during protein translation, is the only protein that requires activation by a unique post-translational hypusine modification. eIF5A hypusination controls cell proliferation and has been linked to cancer. eIF5A hypusination requires the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase and uniquely depends on the polyamine (PA) spermidine as the sole substrate. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in PA biosynthesis. Both ODC and PAs control cell proliferation and are frequently dysregulated in cancer. Since only spermidine can activate eIF5A, we chose the hypusine-PA nexus as a rational target to identify new drug combinations with synergistic antiproliferative effects. We show that elevated mRNA levels of the two target enzymes DHPS and ODC correlate with poor prognosis in a large cohort of neuroblastoma (NB) tumors. The DHPS inhibitor GC7 (N1-guanyl-1,7-diaminoheptane) and the ODC inhibitor α-difluoromethylornithine (DFMO) are target-specific and in combination induced synergistic effects in NB at concentrations that were not individually cytotoxic. Strikingly, while each drug alone at higher con...Continue Reading

References

Sep 1, 1976·Journal of the National Cancer Institute·J L Biedler, B A Spengler
Jul 4, 1990·Journal of the National Cancer Institute·P SkehanM R Boyd
May 1, 1981·Proceedings of the National Academy of Sciences of the United States of America·M H ParkJ E Folk
Apr 27, 1999·The International Journal of Biochemistry & Cell Biology·L M Shantz, A E Pegg
Mar 4, 2003·Nature Reviews. Cancer·Garrett M Brodeur
Sep 19, 2003·The Biochemical Journal·Heather M WallaceAlun Hughes
Sep 21, 2004·The Biochemical Journal·Kazuhiro NishimuraKazuei Igarashi
Oct 8, 2004·Critical Care : the Official Journal of the Critical Care Forum·Viv BewickJonathan Ball
Mar 8, 2006·The FEBS Journal·Paul M J ClementMyung H Park
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Yunfei HuangSolomon H Snyder
Apr 5, 2007·Nature Protocols·Vanicha Vichai, Kanyawim Kirtikara
Apr 28, 2007·Nature Reviews. Drug Discovery·Robert A Casero, Laurence J Marton
Jun 21, 2007·Amino Acids·C F Zanelli, S R Valentini
Jun 26, 2007·Lancet·John M MarisSusan L Cohn
Jan 17, 2009·Cancer Research·Robert J RounbehlerJohn L Cleveland
May 9, 2009·Nature·Preeti SainiThomas E Dever
Oct 1, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nicholas F Evageliou, Michael D Hogarty
Dec 5, 2009·International Journal of Cancer. Journal International Du Cancer·Dirk GeertsAndré S Bachmann
Jun 19, 2010·The New England Journal of Medicine·John M Maris
Jun 23, 2012·Nature·Claudio ScuoppoScott W Lowe
Feb 27, 2013·International Journal of Oncology·Dana-Lynn T KoomoaAndré S Bachmann
Jun 4, 2013·Molecular Cell·Erik GutierrezThomas E Dever
Jul 1, 2010·Drug Discovery Today. Technologies
May 17, 2015·Biochimica Et Biophysica Acta·Michael B Mathews, John W B Hershey
Jun 26, 2015·Genome Biology·Wenqian ZhangMatthias Fischer
Feb 3, 2016·Translational Pediatrics·Hamid BassiriMichael D Hogarty
Mar 26, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nicholas F EvageliouMichael D Hogarty
Jun 9, 2016·The Journal of Biological Chemistry·Anthony E Pegg
Jul 1, 2016·Amino Acids·Shima Nakanishi, John L Cleveland
Sep 30, 2016·The Biochemical Journal·Tracy R Murray-StewartRobert A Casero
Nov 11, 2016·Nature Reviews. Disease Primers·Katherine K MatthayWilliam A Weiss

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Citations

Sep 22, 2018·American Journal of Medical Genetics. Part a·Caleb P BuppAndré S Bachmann
Nov 9, 2018·The Journal of Biological Chemistry·André S Bachmann, Dirk Geerts
Sep 28, 2018·The Journal of Biological Chemistry·Myung Hee Park, Edith C Wolff
Dec 4, 2019·Current Opinion in Pediatrics·Sameer H Issaq, Christine M Heske
Sep 6, 2018·Nature Reviews. Cancer·Robert A CaseroAnthony E Pegg
Jan 19, 2021·Journal of Cellular Biochemistry·Karina D PereiraAugusto D Luchessi
Jun 16, 2021·Cancer Chemotherapy and Pharmacology·Chad R SchultzAndré S Bachmann
Jul 14, 2021·Expert Opinion on Pharmacotherapy·Parmida Sadat PezeshkiNima Rezaei
Aug 14, 2020·Journal of Natural Products·Chad R SchultzAndré S Bachmann
Sep 1, 2021·European Journal of Pharmacology·Qi-Zhang LiYan Ji

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