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Polyamine metabolism and cancer: treatments, challenges and opportunities

Nature Reviews Cancer volume 18, pages 681–695 (2018)Cite this article

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Abstract

Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between polyamine metabolism and other cancer-driving pathways, including the PTEN–PI3K–mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, polyamine blocking therapy, a strategy that combines the inhibition of polyamine biosynthesis with the simultaneous blockade of polyamine transport, can be more effective than therapies based on polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant polyamine metabolism for anticancer therapy.

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Fig. 1: The polyamine metabolic pathway and ATP and methionine salvage pathways.
Fig. 2: Hypusination of eukaryotic initiation factor 5A isoform 1 plays critical roles in both normal and neoplastic cell proliferation.
Fig. 3: Regulation of ornithine decarboxylase by antizyme 1.

Figure adapted with permission from ref.17, Portland Press.

Fig. 4: mTOR complex 1 controls polyamine metabolism.

Figure adapted from ref.46, Springer Nature Limited.

Fig. 5: Polyamine analogue-based nanoparticles with drug cargo as antitumour therapy.

Figure adapted with permission from ref.151, Elsevier.

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References

  1. Pegg, A. E. & Casero, R. A. Jr. Current status of the polyamine research field. Methods Mol. Biol. 720, 3–35 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Terui, Y. et al. Polyamines protect nucleic acids against depurination. Int. J. Biochem. Cell Biol. 99, 147–153 (2018).

    CAS  PubMed  Google Scholar 

  3. Kurata, H. T., Akrouh, A., Li, J. B., Marton, L. J. & Nichols, C. G. Scanning the topography of polyamine blocker binding in an inwardly rectifying potassium channel. J. Biol. Chem. 288, 6591–6601 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Rao, J. N. et al. Polyamines regulate intestinal epithelial restitution through TRPC1-mediated Ca(2)+ signaling by differentially modulating STIM1 and STIM2. Am. J. Physiol. Cell Physiol. 303, C308–C317 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Murray-Stewart, T. R., Woster, P. M. & Casero, R. A. Jr. Targeting polyamine metabolism for cancer therapy and prevention. Biochem. J. 473, 2937–2953 (2016).

    CAS  PubMed  Google Scholar 

  6. Mandal, A., Mandal, S. & Park, M. H. Genome-wide analyses and functional classification of proline repeat-rich proteins: potential role of eIF5A in eukaryotic evolution. PLOS ONE 9, e111800 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Park, M. H., Nishimura, K., Zanelli, C. F. & Valentini, S. R. Functional significance of eIF5A and its hypusine modification in eukaryotes. Amino Acids 38, 491–500 (2010).

    CAS  PubMed  Google Scholar 

  8. Shin, B. S. et al. Amino acid substrates impose polyamine, eIF5A, or hypusine requirement for peptide synthesis. Nucleic Acids Res. 45, 8392–8402 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nakanishi, S. & Cleveland, J. L. Targeting the polyamine-hypusine circuit for the prevention and treatment of cancer. Amino Acids 48, 2353–2362 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Huter, P. et al. Structural basis for polyproline-mediated ribosome stalling and rescue by the translation elongation factor EF-P. Mol. Cell 68, 515–527 (2017).

    CAS  PubMed  Google Scholar 

  11. Pelechano, V. & Alepuz, P. eIF5A facilitates translation termination globally and promotes the elongation of many non polyproline-specific tripeptide sequences. Nucleic Acids Res. 45, 7326–7338 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hoque, M. et al. Regulation of gene expression by translation factor eIF5A: hypusine-modified eIF5A enhances nonsense-mediated mRNA decay in human cells. Translation 5, e1366294 (2017).

    PubMed  PubMed Central  Google Scholar 

  13. Mathews, M. B. & Hershey, J. W. The translation factor eIF5A and human cancer. Biochim. Biophys. Acta 1849, 836–844 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ikeguchi, Y., Bewley, M. C. & Pegg, A. E. Aminopropyltransferases: function, structure and genetics. J. Biochem. 139, 1–9 (2006).

    CAS  PubMed  Google Scholar 

  15. Pegg, A. E. Regulation of ornithine decarboxylase. J. Biol. Chem. 281, 14529–14532 (2006).

    CAS  PubMed  Google Scholar 

  16. Pegg, A. E. S-adenosylmethionine decarboxylase. Essays Biochem. 46, 25–45 (2009).

    CAS  PubMed  Google Scholar 

  17. Kahana, C. Protein degradation, the main hub in the regulation of cellular polyamines. Biochem. J. 473, 4551–4558 (2016).

    CAS  PubMed  Google Scholar 

  18. Wu, H. Y. et al. Structural basis of antizyme-mediated regulation of polyamine homeostasis. Proc. Natl Acad. Sci. USA 112, 11229–11234 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kahana, C. Antizyme and antizyme inhibitor, a regulatory tango. Cell. Mol. Life Sci. 66, 2479–2488 (2009).

    CAS  PubMed  Google Scholar 

  20. Yordanova, M. M. et al. AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation. Nature 553, 356–360 (2018).

    CAS  PubMed  Google Scholar 

  21. Casero, R. A. & Pegg, A. E. Polyamine catabolism and disease. Biochem. J. 421, 323–338 (2009).

    CAS  PubMed  Google Scholar 

  22. Pegg, A. E. Spermidine/spermine-N(1)-acetyltransferase: a key metabolic regulator. Am. J. Physiol. Endocrinol. Metab. 294, E995–E1010 (2008).

    CAS  PubMed  Google Scholar 

  23. Pegg, A. E. Toxicity of polyamines and their metabolic products. Chem. Res. Toxicol. 26, 1782–1800 (2013).

    CAS  PubMed  Google Scholar 

  24. Masuko, T. et al. N(1)-Nonyl-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice. Neurosci. Lett. 13, 118–122 (2018).

    Google Scholar 

  25. Albers, E. Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5′-methylthioadenosine. IUBMB Life 61, 1132–1142 (2009).

    CAS  PubMed  Google Scholar 

  26. Bertino, J. R., Waud, W. R., Parker, W. B. & Lubin, M. Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies. Cancer Biol. Ther. 11, 627–632 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Poulin, R., Casero, R. A. & Soulet, D. Recent advances in the molecular biology of metazoan polyamine transport. Amino Acids 42, 711–723 (2012).

    CAS  PubMed  Google Scholar 

  28. Soulet, D., Gagnon, B., Rivest, S., Audette, M. & Poulin, R. A fluorescent probe of polyamine transport accumulates into intracellular acidic vesicles via a two-step mechanism. J. Biol. Chem. 279, 49355–49366 (2004).

    CAS  PubMed  Google Scholar 

  29. Belting, M. et al. Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide. J. Biol. Chem. 278, 47181–47189 (2003).

    CAS  PubMed  Google Scholar 

  30. Uemura, T., Stringer, D. E., Blohm-Mangone, K. A. & Gerner, E. W. Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G517–G522 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kahana, C. Regulation of cellular polyamine levels and cellular proliferation by antizyme and antizyme inhibitor. Essays Biochem. 46, 47–61 (2009).

    CAS  PubMed  Google Scholar 

  32. Bello-Fernandez, C., Packham, G. & Cleveland, J. L. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc. Natl Acad. Sci. USA 90, 7804–7808 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ozfiliz, P. et al. Bag-1 promotes cell survival through c-Myc-mediated ODC upregulation that is not preferred under apoptotic stimuli in MCF-7 cells. Cell Biochem. Funct. 33, 293–307 (2015).

    CAS  PubMed  Google Scholar 

  34. Koomoa, D. L. et al. DFMO/eflornithine inhibits migration and invasion downstream of MYCN and involves p27Kip1 activity in neuroblastoma. Int. J. Oncol. 42, 1219–1228 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Funakoshi-Tago, M., Sumi, K., Kasahara, T. & Tago, K. Critical roles of Myc-ODC axis in the cellular transformation induced by myeloproliferative neoplasm-associated JAK2 V617F mutant. PLOS ONE 8, e52844 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hogarty, M. D. et al. ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Res. 68, 9735–9745 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Rimpi, S. & Nilsson, J. A. Metabolic enzymes regulated by the Myc oncogene are possible targets for chemotherapy or chemoprevention. Biochem. Soc. Trans. 35, 305–310 (2007).

    CAS  PubMed  Google Scholar 

  38. Roy, U. K., Rial, N. S., Kachel, K. L. & Gerner, E. W. Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis. Mol. Carcinog. 47, 538–553 (2008).

    CAS  PubMed  Google Scholar 

  39. Ignatenko, N. A., Babbar, N., Mehta, D., Casero, R. A. Jr & Gerner, E. W. Suppression of polyamine catabolism by activated Ki-ras in human colon cancer cells. Mol. Carcinog. 39, 91–102 (2004).

    CAS  PubMed  Google Scholar 

  40. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    CAS  PubMed  Google Scholar 

  41. Solit, D. B. & Rosen, N. Resistance to BRAF inhibition in melanomas. N. Engl. J. Med. 364, 772–774 (2011).

    CAS  PubMed  Google Scholar 

  42. Peters, M. C., Minton, A., Phanstiel Iv, O. & Gilmour, S. K. A. Novel polyamine-targeted therapy for BRAF mutant melanoma tumors. Med. Sci. 6, https://doi.org/10.3390/medsci6010003 (2018).

    PubMed Central  Google Scholar 

  43. Kucharzewska, P., Welch, J. E., Svensson, K. J. & Belting, M. The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1. Biochem. Biophys. Res. Commun. 380, 413–418 (2009).

    CAS  PubMed  Google Scholar 

  44. Wang, C. et al. Spermidine/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT/beta-catenin signaling pathways in hepatocellular and colorectal carcinoma cells. Oncotarget 8, 1092–1109 (2017).

    PubMed  Google Scholar 

  45. Zabala-Letona, A. et al. Corrigendum: mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 554, 554 (2018).

    CAS  PubMed  Google Scholar 

  46. Zabala-Letona, A. et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547, 109–113 (2017). This is an important new study describing the dysregulation of AdoMetDC in prostate cancer and suggesting new targets for therapeutic intervention.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Gomes, A. P., Schild, T. & Blenis, J. Adding polyamine metabolism to the mTORC1 toolkit in cell growth and cancer. Dev. Cell 42, 112–114 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tomasi, M. L. et al. Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer. Exp. Cell Res. 319, 1902–1911 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. D’Amico, D. et al. Non-canonical hedgehog/AMPK-mediated control of polyamine metabolism supports neuronal and medulloblastoma cell growth. Dev. Cell 35, 21–35 (2015).

    PubMed  PubMed Central  Google Scholar 

  50. Sandsmark, E. et al. A novel non-canonical Wnt signature for prostate cancer aggressiveness. Oncotarget 8, 9572–9586 (2017).

    PubMed  Google Scholar 

  51. Ou, Y., Wang, S. J., Li, D., Chu, B. & Gu, W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl Acad. Sci. USA 113, E6806–E6812 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cao, J. Y. & Dixon, S. J. Mechanisms of ferroptosis. Cell. Mol. Life Sci. 73, 2195–2209 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Tormey, D. C. et al. Biological markers in breast carcinoma. I. Incidence of abnormalities of CEA, HCG, three polyamines, and three minor nucleosides. Cancer 35, 1095–1100 (1975).

    CAS  PubMed  Google Scholar 

  54. Miolo, G. et al. Pharmacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer. Oncotarget 7, 39809–39822 (2016).

    PubMed  PubMed Central  Google Scholar 

  55. Liu, R. et al. Plasma N-acetylputrescine, cadaverine and 1,3-diaminopropane: potential biomarkers of lung cancer used to evaluate the efficacy of anticancer drugs. Oncotarget 8, 88575–88585 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. Xu, H. et al. Polyamine metabolites profiling for characterization of lung and liver cancer using an LC-tandem MS method with multiple statistical data mining strategies: discovering potential cancer biomarkers in human plasma and urine. Molecules 21, E1040 (2016).

    PubMed  Google Scholar 

  57. Kato, M. et al. Prognostic significance of urine N1, N12-diacetylspermine in patients with non-small cell lung cancer. Anticancer Res. 34, 3053–3059 (2014).

    CAS  PubMed  Google Scholar 

  58. Takahashi, Y. et al. Urinary N1, N12-diacetylspermine is a non-invasive marker for the diagnosis and prognosis of non-small-cell lung cancer. Br. J. Cancer 113, 1493–1501 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Niemi, R. J. et al. Urinary polyamines as biomarkers for ovarian cancer. Int. J. Gynecol. Cancer 27, 1360–1366 (2017).

    PubMed  Google Scholar 

  60. Dejea, C. M. & Sears, C. L. Do biofilms confer a pro-carcinogenic state? Gut Microbes 7, 54–57 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Johnson, C. H. et al. Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab. 21, 891–897 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Nakajima, T. et al. Urinary polyamine biomarker panels with machine-learning differentiated colorectal cancers, benign disease, and healthy controls. Int. J. Mol. Sci. 19, E756 (2018). This paper describes a novel approach to improve the use of polyamine biomarker panels in determining disease states in detection of colon cancers.

    PubMed  Google Scholar 

  63. Liu, R., Lin, X., Li, Z., Li, Q. & Bi, K. Quantitative metabolomics for investigating the value of polyamines in the early diagnosis and therapy of colorectal cancer. Oncotarget 9, 4583–4592 (2018).

    PubMed  Google Scholar 

  64. Asai, Y. et al. Elevated polyamines in saliva of pancreatic cancer. Cancers 10, E43 (2018).

    PubMed  Google Scholar 

  65. Fitzgerald, B. L. et al. Elucidating the structure of N(1)-acetylisoputreanine: a novel polyamine catabolite in human urine. ACS Omega 2, 3921–3930 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Giskeodegard, G. F. et al. Spermine and citrate as metabolic biomarkers for assessing prostate cancer aggressiveness. PLOS ONE 8, e62375 (2013).

    PubMed  PubMed Central  Google Scholar 

  67. Millward, M. J. et al. Multi-centre phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma. Invest. New Drugs 23, 253–256 (2005).

    CAS  PubMed  Google Scholar 

  68. Kadariya, Y. et al. Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T cell lymphoma. Cancer Res. 69, 5961–5969 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Evageliou, N. F. et al. Polyamine antagonist therapies inhibit neuroblastoma initiation and progression. Clin. Cancer Res. 22, 4391–4404 (2016). This paper describes the underlying rationale for and the current status of clinical trials of inhibitors of polyamine biosynthesis in the treatment of neuroblastomas.

    CAS  PubMed  Google Scholar 

  70. Cheng, X. Y. et al. Deletion and downregulation of MTAP contribute to the motility of esophageal squamous carcinoma cells. Onco Targets Ther. 10, 5855–5862 (2017).

    PubMed  PubMed Central  Google Scholar 

  71. Chaturvedi, S., Hoffman, R. M. & Bertino, J. R. Exploiting methionine restriction for cancer treatment. Biochem. Pharmacol. 154, 170–173 (2018).

    CAS  PubMed  Google Scholar 

  72. Tang, B., Lee, H. O., An, S. S., Cai, K. Q. & Kruger, W. D. Specific targeting of MTAP-deleted tumors with a combination of 2-fluoroadenine and 5′-methylthioadenosine. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-18-0814 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016). This paper provides a description of the novel targeting of methylthioadenosine metabolism.

    CAS  PubMed  Google Scholar 

  74. Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).

    CAS  PubMed  Google Scholar 

  75. Bistulfi, G. et al. The essential role of methylthioadenosine phosphorylase in prostate cancer. Oncotarget 7, 14380–14393 (2016).

    PubMed  PubMed Central  Google Scholar 

  76. Evans, G. B. et al. Tight binding enantiomers of pre-clinical drug candidates. Bioorg. Med. Chem. 23, 5326–5333 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Basu, I. et al. Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5′-methylthioadenosine phosphorylase. J. Biol. Chem. 286, 4902–4911 (2011).

    CAS  PubMed  Google Scholar 

  78. Qu, N. et al. Inhibition of human ornithine decarboxylase activity by enantiomers of difluoromethylornithine. Biochem. J. 375, 465–470 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Danzin, C., Casara, P., Claverie, N., Metcalf, B. W. & Jung, M. J. (2R,5R)-6-heptyne-2,5-diamine, an extremely potent inhibitor of mammalian ornithine decarboxylase. Biochem. Biophys. Res. Commun. 116, 237–243 (1983).

    CAS  PubMed  Google Scholar 

  80. Mamont, P. S., Duchesne, M. C., Grove, J. & Bey, P. Anti-proliferative properties of DL-alpha-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase. Biochem. Biophys. Res. Commun. 81, 58–66 (1978).

    CAS  PubMed  Google Scholar 

  81. Levin, V. A., Ictech, S. E. & Hess, K. R. Clinical importance of eflornithine (alpha-difluoromethylornithine) for the treatment of malignant gliomas. CNS Oncol. 7, CNS16 (2018). This paper provides an excellent description of the historical and current attempts to treat glioblastomas and other brain tumours with antagonists of polyamine biosynthesis.

    PubMed  PubMed Central  Google Scholar 

  82. Bassiri, H. et al. Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. Transl Pediatr. 4, 226–238 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. Saulnier Sholler, G. L. et al. A phase I trial of DFMO targeting polyamine addiction in patients with relapsed/refractory neuroblastoma. PLOS ONE 10, e0127246 (2015).

    PubMed  PubMed Central  Google Scholar 

  84. Laukaitis, C. M., Erdman, S. H. & Gerner, E. W. Chemoprevention in patients with genetic risk of colorectal cancers. Colorectal Cancer 1, 225–240 (2012).

    PubMed  PubMed Central  Google Scholar 

  85. Raj, K. P. et al. Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas. Br. J. Cancer 108, 512–518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

    PubMed  Google Scholar 

  87. Kennedy, P. G. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol. 12, 186–194 (2013).

    PubMed  Google Scholar 

  88. Vissing, A. C., Taudorf, E. H., Haak, C. S., Philipsen, P. A. & Haedersdal, M. Adjuvant eflornithine to maintain IPL-induced hair reduction in women with facial hirsutism: a randomized controlled trial. J. Eur. Acad. Dermatol. Venereol. 30, 314–319 (2016).

    CAS  PubMed  Google Scholar 

  89. Rounbehler, R. J. et al. Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma. Cancer Res. 69, 547–553 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Gamble, L. D. et al. Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma. Front. Oncol. 2, 162 (2012).

    PubMed  PubMed Central  Google Scholar 

  91. Geerts, D. et al. The polyamine metabolism genes ornithine decarboxylase and antizyme 2 predict aggressive behavior in neuroblastomas with and without MYCN amplification. Int. J. Cancer 126, 2012–2024 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Depuydt, P. et al. Genomic amplifications and distal 6q loss: novel markers for poor survival in high-risk neuroblastoma patients. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djy022 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Schultz, C. R. et al. Synergistic drug combination GC7/DFMO suppresses hypusine/spermidine-dependent eIF5A activation and induces apoptotic cell death in neuroblastoma. Biochem. J. 475, 531–545 (2018). This paper describes preclinical studies combining an inhibitor of hypusine synthesis with an inhibitor of polyamine synthesis and demonstrates synergy with the combination.

    CAS  PubMed  Google Scholar 

  94. Fujimura, K. et al. Eukaryotic translation initiation factor 5A (EIF5A) regulates pancreatic cancer metastasis by modulating RhoA and Rho-associated kinase (ROCK) protein expression levels. J. Biol. Chem. 290, 29907–29919 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Muramatsu, T. et al. The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. Oncogene 35, 5304–5316 (2016).

    CAS  PubMed  Google Scholar 

  96. Sarhan, S., Knodgen, B. & Seiler, N. The gastrointestinal tract as polyamine source for tumor growth. Anticancer Res. 9, 215–223 (1989).

    CAS  PubMed  Google Scholar 

  97. Burns, M. R., Graminski, G. F., Weeks, R. S., Chen, Y. & O’Brien, T. G. Lipophilic lysine-spermine conjugates are potent polyamine transport inhibitors for use in combination with a polyamine biosynthesis inhibitor. J. Med. Chem. 52, 1983–1993 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Weeks, R. S. et al. Novel lysine-spermine conjugate inhibits polyamine transport and inhibits cell growth when given with DFMO. Exp. Cell Res. 261, 293–302 (2000).

    CAS  PubMed  Google Scholar 

  99. Samal, K. et al. AMXT-1501, a novel polyamine transport inhibitor, synergizes with DFMO in inhibiting neuroblastoma cell proliferation by targeting both ornithine decarboxylase and polyamine transport. Int. J. Cancer 133, 1323–1333 (2013).

    CAS  PubMed  Google Scholar 

  100. Gitto, S. B. et al. Difluoromethylornithine combined with a polyamine transport inhibitor is effective against gemcitabine resistant pancreatic cancer. Mol. Pharm. 15, 369–376 (2018). This paper provides a description of the successful use of the polyamine blocking therapy strategy in the treatment of a pancreatic ductal carcinoma model.

    CAS  PubMed  Google Scholar 

  101. Hayes, C. S. et al. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol. Res. 2, 274–285 (2014).

    CAS  PubMed  Google Scholar 

  102. Alexander, E. T., Minton, A., Peters, M. C., Phanstiel, O. t. & Gilmour, S. K. A novel polyamine blockade therapy activates an anti-tumor immune response. Oncotarget 8, 84140–84152 (2017).

    PubMed  PubMed Central  Google Scholar 

  103. Singh, K. et al. Ornithine decarboxylase in macrophages exacerbates colitis and promotes colitis-associated colon carcinogenesis by impairing M1 immune responses. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-18-0116 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Hardbower, D. M. et al. Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc. Natl Acad. Sci. USA 114, E751–E760 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Chaturvedi, R. et al. Polyamines impair immunity to Helicobacter pylori by inhibiting L-arginine uptake required for nitric oxide production. Gastroenterology 139, 1686–1698 (2010).

    CAS  PubMed  Google Scholar 

  106. Chaturvedi, R., de Sablet, T., Coburn, L. A., Gobert, A. P. & Wilson, K. T. Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis. Amino Acids 42, 627–640 (2012).

    CAS  PubMed  Google Scholar 

  107. Hesterberg, R. S., Cleveland, J. L. & Epling-Burnette, P. K. Role of polyamines in immune cell functions. Med. Sci. 6, E22 (2018).

    Google Scholar 

  108. Feith, D. J., Pegg, A. E. & Fong, L. Y. Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice. Carcinogenesis 34, 570–576 (2013).

    CAS  PubMed  Google Scholar 

  109. Feith, D. J. et al. Mouse skin chemical carcinogenesis is inhibited by antizyme in promotion-sensitive and promotion-resistant genetic backgrounds. Mol. Carcinog. 46, 453–465 (2007).

    CAS  PubMed  Google Scholar 

  110. Nowotarski, S. L., Feith, D. J. & Shantz, L. M. Skin carcinogenesis studies using mouse models with altered polyamines. Cancer Growth Metastasis 8, 17–27 (2015).

    PubMed  PubMed Central  Google Scholar 

  111. Gilmour, S. K. Polyamines and nonmelanoma skin cancer. Toxicol. Appl. Pharmacol. 224, 249–256 (2007).

    CAS  PubMed  Google Scholar 

  112. Guo, Y., Cleveland, J. L. & O’Brien, T. G. Haploinsufficiency for ODC modifies mouse skin tumor susceptibility. Cancer Res. 65, 1146–1149 (2005).

    CAS  PubMed  Google Scholar 

  113. Meyskens, F. L. Jr et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev. Res. 1, 32–38 (2008). This study shows the effectiveness of the combination of an NSAID with DFMO in the prevention of sporadic colorectal adenomas.

    CAS  Google Scholar 

  114. Zell, J. A. et al. Role of obesity in a randomized placebo-controlled trial of difluoromethylornithine (DFMO) + sulindac for the prevention of sporadic colorectal adenomas. Cancer Causes Control 23, 1739–1744 (2012).

    PubMed  PubMed Central  Google Scholar 

  115. Chandra, S., Nymeyer, A. C., Rice, P. F., Gerner, E. W. & Barton, J. K. Intermittent dosing with sulindac provides effective colorectal cancer chemoprevention in the azoxymethane-treated mouse model. Cancer Prev. Res. 10, 459–466 (2017).

    CAS  Google Scholar 

  116. Sinicrope, F. A. et al. Evaluation of difluoromethylornithine for the chemoprevention of Barrett’s esophagus and mucosal dysplasia. Cancer Prev. Res. 4, 829–839 (2011).

    CAS  Google Scholar 

  117. Witherspoon, M., Chen, Q., Kopelovich, L., Gross, S. S. & Lipkin, S. M. Unbiased metabolite profiling indicates that a diminished thymidine pool is the underlying mechanism of colon cancer chemoprevention by alpha-difluoromethylornithine. Cancer Discov. 3, 1072–1081 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Meyskens, F. L. Jr, Simoneau, A. R. & Gerner, E. W. Chemoprevention of prostate cancer with the polyamine synthesis inhibitor difluoromethylornithine. Recent Results Cancer Res. 202, 115–120 (2014).

    CAS  PubMed  Google Scholar 

  119. Xu, H. et al. Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis. Cancer Res. 64, 8521–8525 (2004).

    CAS  PubMed  Google Scholar 

  120. Babbar, N. & Casero, R. A. Jr. Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis. Cancer Res. 66, 11125–11130 (2006).

    CAS  PubMed  Google Scholar 

  121. Goodwin, A. C. et al. Increased spermine oxidase expression in human prostate cancer and prostatic intraepithelial neoplasia tissues. Prostate 68, 766–772 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Chaturvedi, R. et al. Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA. Gastroenterology 141, 1696–1708 (2011).

    CAS  PubMed  Google Scholar 

  123. Goodwin, A. C. et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl Acad. Sci. USA 108, 15354–15359 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Hong, S. K. et al. Increased expression and cellular localization of spermine oxidase in ulcerative colitis and relationship to disease activity. Inflamm. Bowel Dis. 16, 1557–1566 (2010).

    PubMed  Google Scholar 

  125. Smirnova, O. A. et al. Hepatitis C virus alters metabolism of biogenic polyamines by affecting expression of key enzymes of their metabolism. Biochem. Biophys. Res. Commun. 483, 904–909 (2017).

    CAS  PubMed  Google Scholar 

  126. Pledgie, A. et al. Spermine oxidase SMO(PAOh1), not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines. J. Biol. Chem. 280, 39843–39851 (2005).

    CAS  PubMed  Google Scholar 

  127. Chaturvedi, R. et al. Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase. Oncogene 34, 3429–3440 (2015).

    CAS  PubMed  Google Scholar 

  128. Murray-Stewart, T. et al. Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer. Oncogene 35, 5480–5488 (2016). This study defines an epigenetic mechanism by which SMOX expression is dysregulated in individuals with Helicobacter pylori infection who are at high risk of developing gastric cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Zahedi, K. et al. Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury. PLOS ONE 12, e0184570 (2017).

    PubMed  PubMed Central  Google Scholar 

  130. Seiler, N. How important is the oxidative degradation of spermine?: minireview article. Amino Acids 26, 317–319 (2004).

    CAS  PubMed  Google Scholar 

  131. Porter, C. W. & Bergeron, R. J. Regulation of polyamine biosynthetic activity by spermidine and spermine analogs — a novel antiproliferative strategy. Adv. Exp. Med. Biol. 250, 677–690 (1988).

    CAS  PubMed  Google Scholar 

  132. Tummala, R. et al. Combination effects of platinum drugs and N1, N11 diethylnorspermine on spermidine/spermine N1-acetyltransferase, polyamines and growth inhibition in A2780 human ovarian carcinoma cells and their oxaliplatin and cisplatin-resistant variants. Cancer Chemother. Pharmacol. 67, 401–414 (2011).

    CAS  PubMed  Google Scholar 

  133. Hector, S. et al. Polyamine catabolism in colorectal cancer cells following treatment with oxaliplatin, 5-fluorouracil and N1, N11 diethylnorspermine. Cancer Chemother. Pharmacol. 62, 517–527 (2008).

    CAS  PubMed  Google Scholar 

  134. Casero, R. A. Jr & Woster, P. M. Recent advances in the development of polyamine analogues as antitumor agents. J. Med. Chem. 52, 4551–4573 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Allen, W. L. et al. The role of spermidine/spermine N1-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells. Mol. Cancer Ther. 6, 128–137 (2007).

    CAS  PubMed  Google Scholar 

  136. Hacker, A., Marton, L. J., Sobolewski, M. & Casero, R. A. Jr. In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells. Cancer Chemother. Pharmacol. 63, 45–53 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Murray-Stewart, T., Hanigan, C. L., Woster, P. M., Marton, L. J. & Casero, R. A. Jr. Histone deacetylase inhibition overcomes drug resistance through a miRNA-dependent mechanism. Mol. Cancer Ther. 12, 2088–2099 (2013).

    CAS  PubMed  Google Scholar 

  138. Smith, M. A. et al. Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program. Pediatr. Blood Cancer 57, 268–274 (2011).

    PubMed  PubMed Central  Google Scholar 

  139. Pledgie-Tracy, A. et al. The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines. Cancer Chemother. Pharmacol. 65, 1067–1081 (2010).

    CAS  PubMed  Google Scholar 

  140. Goyal, L. et al. Phase 1 study of N(1),N(11)diethylnorspermine (DENSPM) in patients with advanced hepatocellular carcinoma. Cancer Chemother. Pharmacol. 72, 1305–1314 (2013).

    CAS  PubMed  Google Scholar 

  141. Wolff, A. C. et al. A phase II study of the polyamine analog N1,N11-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer. Clin. Cancer Res. 9, 5922–5928 (2003).

    CAS  PubMed  Google Scholar 

  142. Hahm, H. A. et al. Phase I study of N(1),N(11)-diethylnorspermine in patients with non-small cell lung cancer. Clin. Cancer Res. 8, 684–690 (2002).

    CAS  PubMed  Google Scholar 

  143. Streiff, R. R. & Bender, J. F. Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies. Invest. New Drugs 19, 29–39 (2001).

    CAS  PubMed  Google Scholar 

  144. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    CAS  PubMed  Google Scholar 

  145. Hosseini, A. & Minucci, S. A comprehensive review of lysine-specific demethylase 1 and its roles in cancer. Epigenomics 9, 1123–1142 (2017).

    CAS  PubMed  Google Scholar 

  146. Huang, Y., Marton, L. J., Woster, P. M. & Casero, R. A. Polyamine analogues targeting epigenetic gene regulation. Essays Biochem. 46, 95–110 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Nowotarski, S. L. et al. Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures. Bioorg. Med. Chem. 23, 1601–1612 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Sharma, S. K. et al. Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. J. Med. Chem. 53, 5197–5212 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Murray-Stewart, T. et al. Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano11047. PLOS ONE 12, e0175917 (2017).

    PubMed  PubMed Central  Google Scholar 

  151. Xie, Y. et al. Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy. J. Control. Release 246, 110–119 (2017). This is the first description of the use of a polyamine analogue as a backbone for nanoparticle construction, which results in a prodrug as a delivery system for therapeutic nucleic acids.

    CAS  PubMed  Google Scholar 

  152. Leeuwenhoek, A. Natis e semine genitali animalculis. Phi. Trans. R. Soc. 12, 1040–1043 (1678).

    Google Scholar 

  153. Flynn, A. T. & Hogarty, M. D. Myc, oncogenic protein translation, and the role of polyamines. Med. Sci. 6, E41 (2018).

    Google Scholar 

  154. Tong, Y. et al. Crystal structure of human eIF5A1: insight into functional similarity of human eIF5A1 and eIF5A2. Proteins 75, 1040–1045 (2009).

    CAS  Google Scholar 

  155. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03536728?term=NCT03536728&rank=1 (2018).

  156. Sfanos, K. S., Isaacs, W. B. & De Marzo, A. M. Infections and inflammation in prostate cancer. Am. J. Clin. Exp. Urol. 1, 3–11 (2013).

    PubMed  PubMed Central  Google Scholar 

  157. Hartnett, L. & Egan, L. J. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis 33, 723–731 (2012).

    CAS  PubMed  Google Scholar 

  158. Arthur, J. C. et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Babbar, N., Murray-Stewart, T. & Casero, R. A. Jr. Inflammation and polyamine catabolism: the good, the bad and the ugly. Biochem. Soc. Trans. 35, 300–304 (2007).

    CAS  PubMed  Google Scholar 

  160. Noto, J. M. & Peek, R. M. Jr. The gastric microbiome, its interaction with Helicobacter pylori, and its potential role in the progression to stomach cancer. PLOS Pathog. 13, e1006573 (2017).

    PubMed  PubMed Central  Google Scholar 

  161. Hardbower, D. M., Peek, R. M. Jr & Wilson, K. T. At the Bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J. Leukoc. Biol. 96, 201–212 (2014).

    PubMed  PubMed Central  Google Scholar 

  162. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Toprak, N. U. et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect. 12, 782–786 (2006).

    CAS  PubMed  Google Scholar 

  164. Ha, H. C. et al. The natural polyamine spermine functions directly as a free radical scavenger. Proc. Natl Acad. Sci. USA 95, 11140–11145 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Murray-Stewart, T. et al. Nuclear localization of human spermine oxidase isoforms — possible implications in drug response and disease etiology. FEBS J. 275, 2795–2806 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. O’Hagan, H. M. et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20, 606–619 (2011).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the Casero laboratory is supported by grants from the US National Institutes of Health (CA204345), the Maryland Cigarette Restitution Fund and the Samuel Waxman Cancer Research Foundation.

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Authors and Affiliations

  1. Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    Robert A. Casero Jr & Tracy Murray Stewart

  2. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA

    Anthony E. Pegg

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All authors researched data for the article, contributed to the discussion of content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Robert A. Casero Jr.

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The authors receive US National Institutes of Health grant support (R.A.C.) and are patent holders (R.A.C. and A.E.P.). T.M.S. declares no competing interests.

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Glossary terms

Cytostasis

The process by which cells stop dividing without dying; it is a common response by normal cells to polyamine depletion, which can then recover growth once the polyamine block is removed.

Hypusine

A unique amino acid found in all eukaryotes and some archaea that is the product of a post-translational modification of a specific lysine (K50 in humans) residue of the transcription factor eukaryotic initiation factor 5A isoform 1 (eIF5A), which is produced by the transfer of the aminobutyl moiety of spermidine to the lysine residue.

5′-methylthioadenosine phosphorylase

(MTAP). The enzyme that catalyses the initial step in methionine and adenosine nucleotide salvage from the methylthioadenosine product of both spermidine and spermine synthesis; the gene coding for this protein is frequently lost or silenced in tumours, thus facilitating a unique biochemical difference that may be exploited in many cancers.

Protonated

The state of having accepted a proton; in the case of polyamines at physiological pH, all imine and amine nitrogens are positively charged.

Proenzyme

The inactive precursor of an active enzyme; S‑adenosylmethionine decarboxylase (AdoMetDC) is a self-processing proenzyme that undergoes an autocatalytic serinolysis to produce the pyruvoyl group necessary for the activity of the mature AdoMetDC enzyme.

Ferroptosis

An iron-dependent programmed cell death process that is characterized by an accumulation of lipid peroxidases.

Prodrug

A formulation of an inactive compound that once metabolized or altered by the cellular environment produces the active form of the drug.

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Casero, R.A., Murray Stewart, T. & Pegg, A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat Rev Cancer 18, 681–695 (2018). https://doi.org/10.1038/s41568-018-0050-3

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