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Hypusinated EIF5A as a feasible drug target for Advanced Medicinal Therapies in the treatment of pathogenic parasites and therapy-resistant tumors

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Abstract

Cancer drug resistance, in particular in advanced stages such as metastasis and invasion is an emerging problem. Moreover, drug resistance of parasites causing poverty-related diseases is an enormous, global challenge for drug development in the future. To circumvent this problem of increasing resistance, the development of either novel small compounds or Advanced Medicinal Therapies have to be fostered. Polyamines have many fundamental cellular functions like DNA stabilization, protein translation, ion channel regulation, autophagy, apoptosis and mostly important, cell proliferation. Consequently, many antiproliferative drugs can be commonly administered either in cancer therapy or for the treatment of pathogenic parasites. Most important for cell proliferation is the triamine spermidine, since it is an important substrate in the biosynthesis of the posttranslational modification hypusine in eukaryotic initiation factor 5A (EIF5A). To date, no small compound has been identified that directly inhibits the precursor protein EIF5A. Moreover, only a few small molecule inhibitors of the two biosynthetic enzymes, i.e. deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) have been functionally characterized. However, it is evident that only some of the compounds have been applied in translational approaches, i.e. in murine models to analyze the function of this modified protein in cell proliferation. In recent years, the pharmaceutical industry shifted from small molecules beyond traditional pharmacology to new tools and methods to treat disorders involving signaling deregulation. In this review, we evaluate translational approaches on inhibition of EIF5A hypusination in pathogenic parasites and therapy-resistant tumors and discuss its feasibility for an application in Advanced Medicinal Therapies.

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Abbreviations

BSAO:

Bovine Serum Amine Oxidase

EIF5A:

Eukaryotic Initiation Factor 5A

CRISPR:

Clustered Regularly Interspaced Short Palindromic Repeats

DHS:

Deoxyhypusine synthase

DOHH:

Deoxyhypusine hydroxylase

HUVEC:

Human umbilical vein endothelial cells

5-LOX:

5-Lipoxygenase

Myc:

Transcription factor, name derives from an Avian virus Myelocytomatosis

PPI:

Protein–protein interaction

PTM:

Posttranslational modification

STAT:

Signal transducers and activators of transcription

TNF-α:

Tumor necrosis factor alpha

WNT:

Signaling pathway for immune cell maintenance and renewal

References

  • Agostinelli E (2014) Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives. Amino Acids 46:475–485. https://doi.org/10.1007/s00726-014-1688-0

    Article  CAS  PubMed  Google Scholar 

  • Agostinelli E, Tempera G, Molinari A, Salvi M, Battaglia V, Toninello A, Arancia G (2007) The physiological role of biogenic amines redox reactions in mitochondria. New Perspect Cancer Therapy Amino Acids 33:175–187

    Article  CAS  Google Scholar 

  • Agostinelli E, Tempera G, Viceconte N, Saccoccio S, Battaglia V, Grancara S, Toninello A, Stevanato R (2010) Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach. Amino Acids 38:353–368

    Article  CAS  PubMed  Google Scholar 

  • Agostinelli E, Condello M, Tempera G, Macone A, Bozzuto G, Ohkubo S, Calcabrini A, Arancia G, Molinari A (2014) The combined treatment with chloroquine and the enzymatic oxidation products of spermine overcomes multidrug resistance of melanoma M14 ADR2 cells: a new therapeutic approach. Int J Oncol 45:1109–1122. https://doi.org/10.3892/ijo.2014.2502

    Article  CAS  PubMed  Google Scholar 

  • Ahmad MZ, Akhter S, Rahman Z, Akhter S, Anwar M, Mallik N, Ahmad FJ (2013) Nanometric gold in cancer nanotechnology: current status and future prospect. J Pharm Pharmacol 65:634–651. https://doi.org/10.1111/jphp.12017

    Article  CAS  PubMed  Google Scholar 

  • Amendola R, Cervelli M, Fratini E, Sallustio DE, Tempera G, Ueshima T, Mariottini P, Agostinelli E (2013) Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments. Int J Oncol 43:813–820. https://doi.org/10.3892/ijo.2013.2013

    Article  CAS  PubMed  Google Scholar 

  • Aroonsri A, Posayapisit N, Kongsee J, Siripan O, Vitsupakorn D, Utaida S, Uthaipibull C, Kamchonwongpaisan S, Shaw PS (2019) Validation of Plasmodium falciparum deoxyhypusine synthase as an antimalarial target. Peer J 7:e6713 (10.771/peerj.6713)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Atemnkeng VA, Pink M, Schmitz-Spanke S, Wu XJ, Dong LL, Zhao KH, May C, Laufer S, Langer B, Kaiser A (2013) Deoxyhypusine hydroxylase from Plasmodium vivax, the neglected human malaria parasite: molecular cloning, expression and specific inhibition by the 5-LOX inhibitor zileuton. PLoS ONE 8(3):e58318. https://doi.org/10.1371/journal.pone.0058318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atkins MB, Redman B, Mier J, Gollob J, Weber J, Sosman J, MacPherson BL, Plasse T (2001) A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-dose interleukin-2 in patients with renal cancer and melanoma. Clin Canc Res 7:486–492

    CAS  Google Scholar 

  • Averill-Bates DA, Cherif A, Agostinelli E, Tanel A, Fortier G (2005) Anti-tumoral effect of native and immobilized bovine serum amine oxidase in a mouse melanoma model. Biochem Pharmacol 69:1693–1704. https://doi.org/10.1016/j.bcp.2005.02.025

    Article  CAS  PubMed  Google Scholar 

  • Bevec D, Hauber J (1997) Eukaryotic initiation factor 5A activity and HIV-1 Rev function. Biol Signals 6(3):124–133. https://doi.org/10.1159/000109118

    Article  CAS  PubMed  Google Scholar 

  • Calcabrini A, Arancia G, Marra M, Crateri P, Befani O, Martone A, Agostinelli E (2002) Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug-resistant colon carcinoma cells (LoVo) than on their wild-type counterparts. Int J Cancer 99(1):43–52

    Article  CAS  PubMed  Google Scholar 

  • Caraglia M, Alaia C, Porcelli M (2014) From protein synthesis to molecular biology. The appealing tale of eIF5A. Mol Ther Nucleic Acids 3:E133. https://doi.org/10.1038/mtna.2014.53

    Article  CAS  Google Scholar 

  • Casero RA Jr, Stewart TM, Pegg AE (2018) Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat Rev Cancer 18:681–695. https://doi.org/10.1038/s41568-018-0050-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coni S, Serrao SM, Yurtsever ZN, Di Magno L, Bordone R, Bertani C, Licursi V, Ianniello Z, Infante P, Moretti M, Petroni M, Guerrieri F, Fatica A, Macone A, De Smaele E, Di Marcotullio L, Giannini G, Maroder M, Agostinelli E, Canettieri G (2020) Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation. Cell Death Dis 11:1045–1058. https://doi.org/10.1038/s41419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Danese S, Semeraro S, Armuzzi A, Papa A, Gasbarrini A (2006) Biological therapies for inflammatory bowel disease: research drives clinics. Mini Rev Med Chem 6:771–784

    Article  CAS  PubMed  Google Scholar 

  • Doane T, Burda C (2012) The unique role of nanoparticles in nanomedicine: imaging, drug delivery and therapy. Chem Soc Rev 41:2885–2911. https://doi.org/10.1039/c2cs15260f

    Article  CAS  PubMed  Google Scholar 

  • Dong Z, Arnold RJ, Yang Y, Park MH, Hrncirova P, Mechref Y, Novotny MV, Zhang JT (2005) Modulation of differentiation-related gene 1 expression by cell cycle blocker mimosine, revealed by proteomic analysis. Mol Cell Proteom 4:993–1001

    Article  CAS  Google Scholar 

  • Doudna JA (2020) The promise and challenge of therapeutic genome editing. Nature 578(7794):229–236. https://doi.org/10.1038/s41586-020-1978-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan B, Wang YZ, Yang T, Chu XP, Yu Y, Huang Y, Cao H, Hansen J, Simon RP, Zhu MX, Xiong ZG, Xu TL (2011) Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J Neurosci 31:2101–2112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Epis MR, Giles KM, Kalinowski FC, Barker A, Cohen RJ, Leedman PJ (2012) Regulation of expression of deoxyhypusine hydroxylase (DOHH), the enzyme that catalyzes the activation of eIF5A, by miR-331-3p and miR-642-5p in prostate cancer cells. J Biol Chem 287(42):35251–35259. https://doi.org/10.1074/jbc.M112.374686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang L, Gao L, Xie L, Xiao G (2018) GC7 enhances cisplatin sensitivity via STAT3 signaling pathway inhibition and eIF5A2 inactivation in mesenchymal phenotype oral cancer cells. Oncol Rep 39:1283–1291

    CAS  PubMed  Google Scholar 

  • Flynn AT, Hogarty MD (2018) Myc oncogenic protein translation and the role of polyamines. Med Sci (basel) 25:41

    Google Scholar 

  • Fratoddi I, Venditti I, Cametti C, Russo M (2014) Gold nanoparticles and gold nanoparticle-conjugates for delivery of therapeutic molecules. Progress and challenges. J Mater Chem B 2:4204–4220. https://doi.org/10.1039/c4tb00383g

    Article  CAS  PubMed  Google Scholar 

  • Ganapathi M, Padgett LR, Yamada K, Devinsky O, Willaert RP et al (2019) Recessive rare variants in deoxyhypusine synthase, an enzyme involved in the synthesis of hypusine, are associated with a neurodevelopmental disorder. Am J Human Genet 104:287–298

    Article  CAS  Google Scholar 

  • Ghorbal M, Gorman M, Macpherson CR, Martins RM, Scherf A, Lopez-Rubio JJ (2014) Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system. Nat Biotechnol 3:819–821

    Article  CAS  Google Scholar 

  • Goncalves M (2014) Plasmonic nanoparticles: fabrication, simulation and experiments. J Phys D Appl Phys 47:213001–213044

    Article  CAS  Google Scholar 

  • Grüber G (2015) The beauty of a visualized peroxo-diiron(III) intermediate. Structure 23(5):805–806

    Article  PubMed  CAS  Google Scholar 

  • Gurevich EV, Gurevich VV (2015) Beyond traditional pharmacology: new tools and approaches. Br J Pharmacol 172:3229–3241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han Z, Sakai N, Böttger LH, Klinke S, Hauber J, Trautwein AX, Hilgenfeld R (2015) Crystal structure of the peroxo-diiron(III) intermediate of deoxyhypusine hydroxylase, an oxygenase involved in hypusination. Structure 23:882–892

    Article  CAS  PubMed  Google Scholar 

  • Hauber I, Bevec D, Heukeshoven J, Krätzer F, Horn F, Choidas A, Harrer T, Hauber J (2005) Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. J Clin Invest 115:76–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoque M, Park JY, Chang YJ, Luchessi AD, Cambiaghi TD, Shamanna R, Hanauske-Abel HM, Holland B, Pe’ery T, Tian B, Mathews MB (2017) Regulation of gene expression by translation factor eIF5A: hypusine-modified eIF5A enhances nonsense-mediated mRNA decay in human cells. Translation (austin). 5(2):e1366294. https://doi.org/10.1080/21690731.2017.1366294

    Article  PubMed  PubMed Central  Google Scholar 

  • Humphries B, Wang Z, Yang C (2020) Rho GTPases: big players in breast cancer initiation, metastasis and therapeutic responses. Cells 9:2167. https://doi.org/10.3390/cells9102167

    Article  CAS  PubMed Central  Google Scholar 

  • Kaiser A, Hammels I, Gottwald A, Nassar M, Zaghloul MS, Motaal BA, Hauber J, Hoerauf A (2007) Modification of eukaryotic initiation factor 5A from Plasmodium vivax by a truncated deoxyhypusine synthase from Plasmodium falciparum: an enzyme with dual enzymatic properties. Bioorg Med Chem 15:6200–6207

    Article  CAS  PubMed  Google Scholar 

  • Kaiser A, Heiss K, Mueller AK, Fimmers R, Matthes J, Njuguna JT (2020) Inhibition of EIF-5A prevents apoptosis in human cardiomyocytes after malaria infection. Amino Acids 52(5):693–710. https://doi.org/10.1007/s00726-020-02843-2

    Article  CAS  PubMed  Google Scholar 

  • Kanamori Y, Finotti A, Di Magno L, Canettieri G, Tahara T, Timeus F, Greco A, Tirassa P, Gasparello J, Fino P, Di Liegro CM, Proia P, Schiera G, Di Liegro I, Gambari R, Agostinelli E (2021) Enzymatic spermine metabolites induce apoptosis associated with increase of p53, caspase-3 and miR-34a in both neuroblastoma cells, SJNKP and the N-Myc-amplified form IMR5. Cells 10:1950–1975. https://doi.org/10.3390/cells10081950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kersting D, Krüger M, Sattler J, Müller AK, Kaiser A (2016) A suggested vital function for eIF-5A and dhs genes during murine malaria blood-stage infection. FEBS Open Bio 8:860–872. https://doi.org/10.1002/2211-5463.12093

    Article  CAS  Google Scholar 

  • Knuepfer E, Napiorkowska M, van Ooij C, Holder AA (2017) Generating conditional gene knockouts in Plasmodium—a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR/Cas9. Sci Rep 7(1):3881. https://doi.org/10.1038/s41598-017-03984-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lana MG, Strauss BE (2020) Production of Lentivirus for the establishment of CAR-T cells. Methods Mol Biol 2086:61–67. https://doi.org/10.1007/978-1-0716-0146-4_4

    Article  CAS  PubMed  Google Scholar 

  • Lee MC, Fidock DA (2014) CRISPR-mediated genome editing of Plasmodium falciparum malaria parasites. Genome Med 6(8):63. https://doi.org/10.1186/s13073-014-0063-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee YB, Park MH, Folk JE (1995) Diamine and triamine analogs and derivatives as inhibitors of deoxyhypusine synthase: synthesis and biological activity. J Med Chem 38:3053–3061

    Article  CAS  PubMed  Google Scholar 

  • Lentini A, Abbruzzese A, Provenzano B, Tabolacci C, Beninati S (2013) Transglutaminases key regulators of cancer metastasis. Amino Acids 44:25–32

    Article  CAS  PubMed  Google Scholar 

  • Littler DR, Bullen HE, Harvey KL, Beddoe T, Crabb BS, Rossjohn J et al (2016) Disrupting the Allosteric Interaction between the Plasmodium falciparum cAMP-dependent Kinase and Its Regulatory Subunit. J Biol Chem 291:25375–25386. https://doi.org/10.1074/jbc.M116.750174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Xue F, Zhang Y, Lei P, Wang Z, Zhu Z, Sun K (2017) N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of acute lymphoblastic leukemia cells to vincristine through inhibition of eif5a-2 activation. Anticancer Drugs 28:1097–1105

    Article  PubMed  CAS  Google Scholar 

  • Maier B, Ogihara T, Trace AP, Tersey SA, Robbins RD, Chakrabarti SK, Nunemaker CS, Stull ND, Taylor CA, Thompson JE, Dondero RS, Lewis EC, Dinarello CA, Nadler JL, Mirmira RG (2010) The unique hypusine modification of eIF5A promotes islet beta cell inflammation and dysfunction in mice. J Clin Invest 120(6):2156–2170. https://doi.org/10.1172/JCI38924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mandal A, Mandal S, Park M (2016) Global quantitative proteomics reveal up-regulation of endoplasmic reticulum stress response proteins upon depletion of eIF5A in HeLa cells. Sci Rep 6:25795. https://doi.org/10.1038/srep25795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Milligan ED, O’Connor KA, Armstrong CB, Hansen MK, Martin D, Tracey KJ, Maier SF, Watkins LR (2001) Systemic administration of CNI-1493, a p38 mitogen-activated protein kinase inhibitor, blocks intrathecal human immunodeficiency virus-1 gp120-induced enhanced pain states in rats. J Pain 2:326–333

    Article  CAS  PubMed  Google Scholar 

  • Mittal N, Morada M, Tripathi P, Gowri VS, Mandal S, Quirch A, Park MH, Yarlett N, Madhubala R (2014) Cryptosporidium parvum has an active hypusine biosynthesis pathway. Mol Chem Parasitol 195:14–22

    Article  CAS  Google Scholar 

  • Montanari E, Capece S, Di Meo C, Meringolo M, Coviello T, Agostinelli E, Matricardi P (2013) Hyaluronic acid nanohydrogels as a useful tool for BSAO immobilization in the treatment of melanoma cancer cells. Macromol Biosci 13:1185–1194

    Article  CAS  PubMed  Google Scholar 

  • Mout R, Moyano D, Rana S, Rotello V (2012) Surface functionalization of nanoparticles for nanomedicine. Chem Soc Rev 41:2539–2544. https://doi.org/10.1039/c2cs15294k

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muramatsu T, Kozaki KI, Imoto S, Yamaguchi R, Tsuda H, Kawano T, Fujiwara N, Morishita M, Miyano S, Inazawa J (2016) The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. Oncogene 35:5304–5316

    Article  CAS  PubMed  Google Scholar 

  • Nadège M, Didac CG, Madeo F (2011) Polyamines in aging and disease. Aging 8:716–732

    Google Scholar 

  • Nishimura K, Yanase T, Nakagawa H, Matsuo S, Ohnishi Y, Yamasaki S (2009) Effect of polyamine-deficient chow on Trypanosoma brucei brucei infection in rats. J Parasitol 95:781–786

    Article  CAS  PubMed  Google Scholar 

  • Noelker C, Stuckenholz V, Reese JP, Alvarez-Fischer D, Sankowski R, Rausch T, Oertel WH, Hartmann A, van Patten S, Al-Abed Y, Bacher M (2013) CNI-1493 attenuates neuroinflammation and dopaminergic neurodegeneration in the acute MPTP mouse model of Parkinson’s disease. Neurodegenr Dis 12:103–110

    Article  CAS  Google Scholar 

  • Ohkubo S, Mancinelli R, Miglietta S, Cona A, Angelini R, Canettieri G, Spandidos DA, Gaudio E, Agostinelli E (2019) Maize polyamine oxidase in the presence of spermine/spermidine induces the apoptosis of LoVo human colon adenocarcinoma cells. Int J Oncol 54:2080–2094

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park JH, Aravind L, Wolff EC, Kaevel J, Kim YS, Park MH (2006) Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci USA 103(1):51–56

    Article  CAS  PubMed  Google Scholar 

  • Park MH, Mandal A, Mandal S, Wolff EC (2017) A new non-radioactive assay adaptable to high-throughput screening. Amino Acids 49:1793–1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pettinger J, Carter M, Jones K, Cheeseman MD (2019) Kinetic optimization of lysine-targeting covalent inhibitors of HSP72. J Med Chem 26:11383–11398

    Article  CAS  Google Scholar 

  • Puleston DJ, Buck MD, Klein Geltink RI, Kyle RL, Caputa G, O’Sullivan D, Cameron AM, Castoldi A, Musa Y, Kabat AM, Zhang Y, Flachsmann LJ, Field CS, Patterson AE, Scherer S, Alfei F, Baixauli F, Austin SK, Kelly B, Matsushita M, Curtis JD, Grzes KM, Villa M, Corrado M, Sanin DE, Qiu J, Pällman N, Paz K, Maccari ME, Blazar BR, Mittler G, Buescher JM, Zehn D, Rospert S, Pearce EJ, Balabanov S, Pearce EL (2019) Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab 30(2):352-363.e8. https://doi.org/10.1016/j.cmet.2019.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintas-Granados LI, Carvajal Gamez BI, Villalpando JL, Ortega-Lopez J, Arroyo R, Azuara-Liceaga E, Álvarez-Sánchez ME (2016) Bifunctional activity of deoxyhypusine synthase/hydroxylase from Trichomonas vaginalis. Biochimie 123:37–41

    Article  CAS  PubMed  Google Scholar 

  • Quintiliani M, Bassetti M, Pasquini C, Battocchio C, Rossi M, Mura F, Matassa R, Fontana L, Russo M, Fratoddi I (2014) Network assembly of gold nanoparticles linked through fluorenyl dithiol bridge. J Mater Chem C 2:2517–2527

    Article  CAS  Google Scholar 

  • Sankowski R, Herring A, Keyvani K, Frenzel K, Wu J, Röskam S, Noelker C, Bacher M, Al-Abed Y (2016) The multi-target effects of CNI-1493: convergence of anti-amylodogenic and anti-inflammatory properties in animal models of Alzheimer’s disease. Mol Med 22:776–788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schröder M, Kolodzik A, Windshügel B, Krepstakies M, Priyadarshini P, Hartjen P, van Lunzen J, Rarey M, Hauber J, Meier C (2016) Linker-Region modified derivatives of the deoxyhypusine synthase Inhibitor CNI-1493 suppress HIV-1 replication. Arch Pharm 349:91–103

    Article  CAS  Google Scholar 

  • Schwentke A, Krepstakies M, Mueller AK, Hammerschmidt-Kamper C, Motaal BA, Bernhard T, Hauber J, Kaiser A (2012) In vitro and in vivo silencing of plasmodial dhs and eIf-5a genes in a putative, non-canonical RNAi-related pathway. BMC Microbiol 13(12):107. https://doi.org/10.1186/1471-2180-12-107

    Article  CAS  Google Scholar 

  • Shen T, Huang S (2016) Repositioning the old fungicide ciclopirox for new medical uses. Curr Pharm Des 22(28):4443–4450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Specht S, Sarite SR, Hauber I, Hauber J, Görbig UF, Meier C, Bevec D, Hoerauf A, Kaiser A (2008) The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria-inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase. Parasitol Res 102:1177–1184

    Article  PubMed  Google Scholar 

  • Tanaka Y, Kurasawa O, Yokota A, Klein MG, Ono K et al (2020) Discovery of novel allosteric inhibitors of deoxyhypusine synthase. J Med Chem 63:3215–3226

    Article  CAS  PubMed  Google Scholar 

  • Tersey SA, Colvin SC, Maier B, Mirmira RG (2014) Protective effects of polyamine depletion in mouse models of type 1 diabetes: implications for therapy. Amino Acids 46(3):633–642. https://doi.org/10.1007/s00726-013-1560-7

    Article  CAS  PubMed  Google Scholar 

  • Tracey KJ (1998) Suppression of TNF and other proinflammatory cytokines by the tetravalent guanylhydrazone CNI-1493. Prog Clin Biol Res 397:335–343

    CAS  PubMed  Google Scholar 

  • Uimari A, Merentie M, Sironen R, Pirnes-Karhu S, Peräniemi S, Alhonen L (2012) Overexpression of spermidine/spermine N1-acetyltransferase or treatment with N1–N11-diethylnorspermine attenuates the severity of zinc-induced pancreatitis in mouse. Amino Acids 42:461–471

    Article  CAS  PubMed  Google Scholar 

  • Umland TC, Wolff EC, Park MH, Davies D (2004) A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme*NAD* inhibitor ternary complex. J Biol Chem 279(27):28697–28705

    Article  CAS  PubMed  Google Scholar 

  • Venditti I, Fontana L, Fratoddi I, Battocchio C, Cametti C, Sennato S, Mura F, Sciubba F, Delfini M, Russo M (2014) Direct interaction of hydrophilic gold nanoparticles with dexamethasone drug: loading and release study. J Colloid Interface Sci 418:52–60

    Article  CAS  PubMed  Google Scholar 

  • Venditti I, Hassanein TF, Fratoddi I, Fontana L, Battocchio C, Rinaldi F, Carafa M, Marianecci C, Diociaiuti M, Agostinelli E et al (2015) Bioconjugation of gold-polymer core-shell nanoparticles with bovine serum amine oxidase for biomedical applications. Colloids Surf B Biointerfaces 134:314–321

    Article  CAS  PubMed  Google Scholar 

  • Von Koschitzky I, Kaiser A (2014) Chemical profiling of deoxyhypusine hydroxylase inhibitors for antimalarial therapy. Amino Acids 45:1047–1053

    Article  CAS  Google Scholar 

  • Von Koschitzky I, Gerhardt H, Lämmerhofer M, Kohout M, Gehringer M, Laufer S, Pink M, Schmitz-Spanke S, Strube C, Kaiser A (2015) New insights into novel inhibitors against deoxyhypusine hydroxylase from Plasmodium falciparum: compounds with an iron chelating potential. Amino Acids 47:1155–1166

    Article  CAS  Google Scholar 

  • Vu VV, Emerson JP, Martinho M, Kim YS, Münck E, Park MH, Que L Jr (2009) Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O2 with a nonheme diiron center. Proc Natl Acad Sci USA 106(35):14814–14819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wallace HM, Fraser AV (2004) Inhibitors of polyamine metabolism: Review article. Amino Acids 26:353–365

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Ma Y, Wang X, Zhang Y, Tan H, Li X, Chen G (2020) Theoretical study on the catalytic mechanism of human deoxyhypusine hydroxylase. Phys Chem Chem Phys 22:22736–22745

    Article  CAS  PubMed  Google Scholar 

  • Xu G, Yu H, Shi X, Sun L, Zhou Q, Zheng D, Shi H, Li N, Zhang X, Shao G (2014) Cisplatin sensitivity is enhanced in non-small cell lung cancer cells by regulating epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2. BMC Pulm Med 14:174

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou QY, Tu CY, Shao CX, Wang WK, Zhu JD, Cai Y, Mao JY, Chen W (2017) GC7 blocks epithelial-mesenchymal transition and reverses hypoxia-induced chemotherapy resistance in hepatocellular carcinoma cells. Am J Transl Res 9:2608–2617

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ziegler P, Chahoud T, Wilhelm T, Pällman N, Braig M, Wiehle V, Ziegler S, Schröder M, Meier C, Kolodzik A, Rarey M, Panse J, Hauber J, Balabanov S, Brümmendorf TH (2012) Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias. Invest New Drugs 30:2274–2283

    Article  CAS  PubMed  Google Scholar 

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Funding

Parts from this work were supported by ERANETPLUS 2019-446-3 to AK. The authors would like to thank the ‘International Polyamine Foundation ETS-ONLUS.

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Authors and Affiliations

  1. Medical Research Centre, University Hospital, University Duisburg-Essen, Hufelandstrasse 55, Essen, 45147, Germany

    Annette Kaiser

  2. Department of Sensory Organs, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155, 00161, Rome, Italy

    Enzo Agostinelli

  3. International Polyamines Foundation ‘ETS-ONLUS’, Via del Forte Tiburtino 98, 00159, Rome, Italy

    Enzo Agostinelli

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  1. Annette Kaiser
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Correspondence to Annette Kaiser.

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Both authors thoroughly edited the manuscript and approved the final draft. E.A. was responsible for the chapter of translational approaches with nanoparticles.

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Kaiser, A., Agostinelli, E. Hypusinated EIF5A as a feasible drug target for Advanced Medicinal Therapies in the treatment of pathogenic parasites and therapy-resistant tumors. Amino Acids 54, 501–511 (2022). https://doi.org/10.1007/s00726-021-03120-6

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