Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic

Subjects

Abstract

The median survival for glioblastoma patients is ~15 months despite aggressive surgery and radio-chemotherapy approaches. Thus, developing new therapeutics is necessary to improve the treatment of these invasive brain tumors, which are known to show high levels of the eukaryotic initiation factor, eIF4E, a potent oncogene. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C treatment. Here, we report the effect of ribavirin on proliferation, cell cycle, cell death and migration of several human and murine glioma cell lines, as well as human glioblastoma stem-like cells, in vitro. In addition, we tested ribavirin efficacy in vivo, alone and in combination with temozolomide and radiation. Our work showed that ribavirin inhibits glioma cell growth and migration, and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E, EZH2 and ERK pathways. We also demonstrate that ribavirin treatment in combination with temozolomide or irradiation increases cell death in glioma cells. Finally and most importantly, ribavirin treatment in vivo significantly enhances chemo-radiotherapy efficacy and improves survival of rats and mice orthotopically implanted with gliosarcoma tumors or glioma stem-like cells, respectively. On the basis of these results, we propose that ribavirin represents a new therapeutic option for glioblastoma patients as an enhancer of the cytotoxic effects of temozolomide and radiotherapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. 1

    Eggleston M . Clinical review of ribavirin. Infect Control 1987; 8: 215–218.

    CAS  Article  Google Scholar 

  2. 2

    Paeshuyse J, Dallmeier K, Neyts J . Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action. Curr Opin Virol 2012; 1: 590–598.

    Article  Google Scholar 

  3. 3

    Zopf S, Kremer AE, Neurath MF, Siebler J . Advances in hepatitis C therapy: what is the current state—what come's next? World J Hepatol 2016; 8: 139–147.

    Article  Google Scholar 

  4. 4

    Loustaud-Ratti V, Debette-Gratien M, Jacques J, Alain S, Marquet P, Sautereau D et al. Ribavirin: past, present and future. World J Hepatol 2016; 8: 123–130.

    Article  Google Scholar 

  5. 5

    Borden KL, Culjkovic-Kraljacic B . Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? Leuk Lymphoma 2010; 51: 1805–1815.

    CAS  Article  Google Scholar 

  6. 6

    De la Cruz-Hernandez E, Medina-Franco JL, Trujillo J, Chavez-Blanco A, Dominguez-Gomez G, Perez-Cardenas E et al. Ribavirin as a tri-targeted antitumor repositioned drug. Oncol Rep 2015; 33: 2384–2392.

    CAS  Article  Google Scholar 

  7. 7

    Assouline S, Culjkovic-Kraljacic B, Bergeron J, Caplan S, Cocolakis E, Lambert C et al. A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E. Haematologica 2014; 100: e7–e9.

    Article  Google Scholar 

  8. 8

    Pettersson F, Yau C, Dobocan MC, Culjkovic-Kraljacic B, Retrouvey H, Puckett R et al. Ribavirin treatment effects on breast cancers overexpressing eIF4E, a biomarker with prognostic specificity for luminal B-type breast cancer. Clin Cancer Res 2011; 17: 2874–2884.

    CAS  Article  Google Scholar 

  9. 9

    Kokeny S, Papp J, Weber G, Vaszko T, Carmona-Saez P, Olah E . Ribavirin acts via multiple pathways in inhibition of leukemic cell proliferation. Anticancer Res 2009; 29: 1971–1980.

    CAS  PubMed  Google Scholar 

  10. 10

    Olah E, Kokeny S, Papp J, Bozsik A, Keszei M . Modulation of cancer pathways by inhibitors of guanylate metabolism. Adv Enzyme Regul 2006; 46: 176–190.

    CAS  Article  Google Scholar 

  11. 11

    Shi F, Len Y, Gong Y, Shi R, Yang X, Naren D et al. Ribavirin inhibits the activity of mTOR/eIF4E, ERK/Mnk1/eIF4E signaling pathway and synergizes with tyrosine kinase inhibitor imatinib to impair Bcr-Abl mediated proliferation and apoptosis in Ph+ leukemia. PLoS One 2015; 10: e0136746.

    Article  Google Scholar 

  12. 12

    Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden KL . Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci USA 2004; 101: 18105–18110.

    CAS  Article  Google Scholar 

  13. 13

    Kentsis A, Volpon L, Topisirovic I, Soll CE, Culjkovic B, Shao L et al. Further evidence that ribavirin interacts with eIF4E. RNA 2005; 11: 1762–1766.

    CAS  Article  Google Scholar 

  14. 14

    Pettersson F, Del Rincon SV, Miller WH Jr . Eukaryotic translation initiation factor 4E as a novel therapeutic target in hematological malignancies and beyond. Expert Opin Ther Targets 2014; 18: 1035–1048.

    CAS  Article  Google Scholar 

  15. 15

    Gu X, Jones L, Lowery-Norberg M, Fowler M . Expression of eukaryotic initiation factor 4E in astrocytic tumors. Appl Immunohistochem Mol Morphol 2005; 13: 178–183.

    CAS  Article  Google Scholar 

  16. 16

    Ruggero D, Pandolfi PP . Does the ribosome translate cancer? Nat Rev Cancer 2003; 3: 179–192.

    CAS  Article  Google Scholar 

  17. 17

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al. The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016; 131: 803–820.

    Article  Google Scholar 

  18. 18

    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459–466.

    CAS  Article  Google Scholar 

  19. 19

    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–996.

    CAS  Article  Google Scholar 

  20. 20

    McGirt MJ, Than KD, Weingart JD, Chaichana KL, Attenello FJ, Olivi A et al. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg 2009; 110: 583–588.

    CAS  Article  Google Scholar 

  21. 21

    Assouline S, Culjkovic B, Cocolakis E, Rousseau C, Beslu N, Amri A et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood 2009; 114: 257–260.

    CAS  Article  Google Scholar 

  22. 22

    Pettersson F, Del Rincon SV, Emond A, Huor B, Ngan E, Ng J et al. Genetic and pharmacologic inhibition of eIF4E reduces breast cancer cell migration, invasion, and metastasis. Cancer Res 2015; 75: 1102–1112.

    CAS  Article  Google Scholar 

  23. 23

    Ogino A, Sano E, Ochiai Y, Yamamuro S, Tashiro S, Yachi K et al. Efficacy of ribavirin against malignant glioma cell lines. Oncol Lett 2014; 8: 2469–2474.

    Article  Google Scholar 

  24. 24

    Richard SM, Martinez Marignac VL . Sensitization to oxaliplatin in HCT116 and HT29 cell lines by metformin and ribavirin and differences in response to mitochondrial glutaminase inhibition. J Cancer Res Ther 2015; 11: 336–340.

    CAS  Article  Google Scholar 

  25. 25

    Vignon C, Debeissat C, Georget MT, Bouscary D, Gyan E, Rosset P et al. Flow cytometric quantification of all phases of the cell cycle and apoptosis in a two-color fluorescence plot. PLoS One 2013; 8: e68425.

    CAS  Article  Google Scholar 

  26. 26

    Zambon AC . Use of the Ki67 promoter to label cell cycle entry in living cells. Cytometry A 2010; 77: 564–570.

    Article  Google Scholar 

  27. 27

    Sesen J, Dahan P, Scotland SJ, Saland E, Dang VT, Lemarie A et al. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS One 2015; 10: e0123721.

    Article  Google Scholar 

  28. 28

    Scheidel LM, Durbin RK, Stollar V . Sindbis virus mutants resistant to mycophenolic acid and ribavirin. Virology 1987; 158: 1–7.

    CAS  Article  Google Scholar 

  29. 29

    Bertolini F, Sukhatme VP, Bouche G . Drug repurposing in oncology–-patient and health systems opportunities. Nat Rev Clin Oncol 2015; 12: 732–742.

    Article  Google Scholar 

  30. 30

    Papanagnou P, Stivarou T, Tsironi M . Unexploited antineoplastic effects of commercially available anti-diabetic drugs. Pharmaceuticals 2016; 9: 24.

    Article  Google Scholar 

  31. 31

    Tamburini J, Green AS, Chapuis N, Bardet V, Lacombe C, Mayeux P et al. Targeting translation in acute myeloid leukemia: a new paradigm for therapy? Cell Cycle 2009; 8: 3893–3899.

    CAS  Article  Google Scholar 

  32. 32

    Ge Y, Zhou F, Chen H, Cui C, Liu D, Li Q et al. Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells. Biochem Biophys Res Commun 2010; 397: 711–717.

    CAS  Article  Google Scholar 

  33. 33

    Vallee S, Fouchier F, Braguer D, Marvaldi J, Champion S . Ribavirin-induced resistance to heat shock, inhibition of the Ras-Raf-1 pathway and arrest in G(1). Eur J Pharmacol 2000; 404: 49–62.

    CAS  Article  Google Scholar 

  34. 34

    Dubois L, Magagnin MG, Cleven AH, Weppler SA, Grenacher B, Landuyt W et al. Inhibition of 4E-BP1 sensitizes U87 glioblastoma xenograft tumors to irradiation by decreasing hypoxia tolerance. Int J Radiat Oncol Biol Phys 2009; 73: 1219–1227.

    CAS  Article  Google Scholar 

  35. 35

    Furic L, Rong L, Larsson O, Koumakpayi IH, Yoshida K, Brueschke A et al. eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc Natl Acad Sci USA 2010; 107: 14134–14139.

    CAS  Article  Google Scholar 

  36. 36

    Grzmil M, Huber RM, Hess D, Frank S, Hynx D, Moncayo G et al. MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas. J Clin Invest 2014; 124: 742–754.

    CAS  Article  Google Scholar 

  37. 37

    Hsieh AC, Ruggero D . Targeting eukaryotic translation initiation factor 4E (eIF4E) in cancer. Clin Cancer Res 2010; 16: 4914–4920.

    CAS  Article  Google Scholar 

  38. 38

    Mijatovic S, Maksimovic-Ivanic D, Radovic J, Miljkovic D, Harhaji L, Vuckovic O et al. Anti-glioma action of aloe emodin: the role of ERK inhibition. Cell Mol Life Sci 2005; 62: 589–598.

    CAS  Article  Google Scholar 

  39. 39

    Sunayama J, Matsuda K, Sato A, Tachibana K, Suzuki K, Narita Y et al. Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells. Stem Cells 2010; 28: 1930–1939.

    CAS  Article  Google Scholar 

  40. 40

    Chen D, Zuo D, Luan C, Liu M, Na M, Ran L et al. Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. PLoS One 2014; 9: e87281.

    Article  Google Scholar 

  41. 41

    Alimova I, Birks DK, Harris PS, Knipstein JA, Venkataraman S, Marquez VE et al. Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells. Neuro Oncol 2013; 15: 149–160.

    CAS  Article  Google Scholar 

  42. 42

    Fan TY, Wang H, Xiang P, Liu YW, Li HZ, Lei BX et al. Inhibition of EZH2 reverses chemotherapeutic drug TMZ chemosensitivity in glioblastoma. Int J Clin Exp Pathol 2014; 7: 6662–6670.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Kim SH, Joshi K, Ezhilarasan R, Myers TR, Siu J, Gu C et al. EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner. Stem Cell Rep 2015; 4: 226–238.

    CAS  Article  Google Scholar 

  44. 44

    Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res 2009; 69: 9211–9218.

    CAS  Article  Google Scholar 

  45. 45

    Zhang W, Lv S, Liu J, Zang Z, Yin J, An N et al. PCI-24781 down-regulates EZH2 expression and then promotes glioma apoptosis by suppressing the PIK3K/Akt/mTOR pathway. Genet Mol Biol 2014; 37: 716–724.

    CAS  Article  Google Scholar 

  46. 46

    Myung JK, Choi SA, Kim SK, Wang KC, Park SH . Snail plays an oncogenic role in glioblastoma by promoting epithelial mesenchymal transition. Int J Clin Exp Pathol 2014; 7: 1977–1987.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Savary K, Caglayan D, Caja L, Tzavlaki K, Bin Nayeem S, Bergstrom T et al. Snail depletes the tumorigenic potential of glioblastoma. Oncogene 2013; 32: 5409–5420.

    CAS  Article  Google Scholar 

  48. 48

    Colombo G, Lorenzini L, Zironi E, Galligioni V, Sonvico F, Balducci AG et al. Brain distribution of ribavirin after intranasal administration. Antiviral Res 2011; 92: 408–414.

    CAS  Article  Google Scholar 

  49. 49

    Jeulin H, Venard V, Carapito D, Finance C, Kedzierewicz F . Effective ribavirin concentration in mice brain using cyclodextrin as a drug carrier: evaluation in a measles encephalitis model. Antiviral Res 2009; 81: 261–266.

    CAS  Article  Google Scholar 

  50. 50

    Dadgostari S, Xu C, Yeh LT, Lin CC, Vitarella D . Viramidine demonstrates better safety than ribavirin in monkeys but not rats. Drug Chem Toxicol 2004; 27: 191–211.

    CAS  Article  Google Scholar 

  51. 51

    Harvie P, Omar RF, Dusserre N, Desormeaux A, Gourde P, Tremblay M et al. Antiviral efficacy and toxicity of ribavirin in murine acquired immunodeficiency syndrome model. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12: 451–461.

    CAS  Article  Google Scholar 

  52. 52

    Narayana K, D'Souza UJ, Seetharama Rao KP . The genotoxic and cytotoxic effects of ribavirin in rat bone marrow. Mutat Res 2002; 521: 179–185.

    CAS  Article  Google Scholar 

  53. 53

    Russmann S, Grattagliano I, Portincasa P, Palmieri VO, Palasciano G . Ribavirin-induced anemia: mechanisms, risk factors and related targets for future research. Curr Med Chem 2006; 13: 3351–3357.

    CAS  Article  Google Scholar 

  54. 54

    Hayman TJ, Williams ES, Jamal M, Shankavaram UT, Camphausen K, Tofilon PJ . Translation initiation factor eIF4E is a target for tumor cell radiosensitization. Cancer Res 2012; 72: 2362–2372.

    CAS  Article  Google Scholar 

  55. 55

    Zekri AR, Bahnasy AA, Shoeab FE, Mohamed WS, El-Dahshan DH, Ali FT et al. Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma. J Adv Res 2015; 5: 27–40.

    Article  Google Scholar 

  56. 56

    Sesen J, Cammas A, Scotland SJ, Elefterion B, Lemarie A, Millevoi S et al. Int6/eIF3e is essential for proliferation and survival of human glioblastoma cells. Int J Mol Sci 2014; 15: 2172–2190.

    Article  Google Scholar 

  57. 57

    Piccirillo SG, Combi R, Cajola L, Patrizi A, Redaelli S, Bentivegna A et al. Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene 2009; 28: 1807–1811.

    CAS  Article  Google Scholar 

  58. 58

    Mangraviti A, Tzeng SY, Gullotti D, Kozielski KL, Kim JE, Seng M et al. Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. Biomaterials 2016; 100: 53–66.

    CAS  Article  Google Scholar 

  59. 59

    Scotland S, Saland E, Skuli N, de Toni F, Boutzen H, Micklow E et al. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia 27: 2129–2138.

  60. 60

    Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S et al. Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood 2009; 114: 469–477.

    CAS  Article  Google Scholar 

  61. 61

    Skuli N, Majmundar AJ, Krock BL, Mesquita RC, Mathew LK, Quinn ZL et al. Endothelial HIF-2alpha regulates murine pathological angiogenesis and revascularization processes. J Clin Invest 2012; 122: 1427–1443.

    CAS  Article  Google Scholar 

  62. 62

    Gallia GL, Tyler BM, Hann CL, Siu IM, Giranda VL, Vescovi AL et al. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 2009; 8: 386–393.

    CAS  Article  Google Scholar 

  63. 63

    Wicks RT, Azadi J, Mangraviti A, Zhang I, Hwang L, Joshi A et al. Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma. Neuro Oncol 2014; 17: 70–80.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the Hunterian Neurosurgical Research Laboratory, Dr Thomas Simon for helpful comments, and Mr and Mrs Peter Jennison and Mr and Mrs Josh Fidler for their kind and generous support. This work was supported by INSERM (Grant number: U1037SPDOTSKULI).

Author information

Affiliations

Authors

Corresponding author

Correspondence to N Skuli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Volpin, F., Casaos, J., Sesen, J. et al. Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic. Oncogene 36, 3037–3047 (2017). https://doi.org/10.1038/onc.2016.457

Download citation

Further reading

Search

Quick links