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Drug repurposing towards targeting cancer stem cells in pediatric brain tumors

  • Hisham F. Bahmad
  • Mohamad K. Elajami
  • Talal El Zarif
  • Jolie Bou-Gharios
  • Tamara Abou-AntounEmail author
  • Wassim Abou-KheirEmail author
Article

Abstract

In the pediatric population, brain tumors represent the most commonly diagnosed solid neoplasms and the leading cause of cancer-related deaths globally. They include low-grade gliomas (LGGs), medulloblastomas (MBs), and other embryonal, ependymal, and neuroectodermal tumors. The mainstay of treatment for most brain tumors includes surgical intervention, radiation therapy, and chemotherapy. However, resistance to conventional therapy is widespread, which contributes to the high mortality rates reported and lack of improvement in patient survival despite advancement in therapeutic research. This has been attributed to the presence of a subpopulation of cells, known as cancer stem cells (CSCs), which reside within the tumor bulk and maintain self-renewal and recurrence potential of the tumor. An emerging promising approach that enables identifying novel therapeutic strategies to target CSCs and overcome therapy resistance is drug repurposing or repositioning. This is based on using previously approved drugs with known pharmacokinetic and pharmacodynamic characteristics for indications other than their traditional ones, like cancer. In this review, we provide a synopsis of the drug repurposing methodologies that have been used in pediatric brain tumors, and we argue how this selective compilation of approaches, with a focus on CSC targeting, could elevate drug repurposing to the next level.

Keywords

Drug repurposing Cancer stem cells Pediatric brain tumors Low-grade glioma Medulloblastoma 

Notes

Acknowledgments

We would like to thank all members in Dr. Abou-Kheir’s Laboratory (The WAK Lab) and Dr. Abou-Antoun’s Laboratory for their help on this work.

Author contributions

WAK and TAA conceived the concept and idea of the present review. HFB, TAA, and WAK worked on the study design strategy and selected the topics to be discussed. HFB and MKE did literature searches and screened titles and abstracts for relevance. HFB, MKE, TEZ, and JB abstracted the data from the eligible full text articles, analyzed and interpreted the data, and drafted the manuscript. TAA and WAK critically revised the manuscript with input from the entire team. All authors have read and approved the final draft.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Pollack, I. F., & Jakacki, R. I. (2011). Childhood brain tumors: epidemiology, current management and future directions. Nature Reviews Neurology, 7(9), 495–506.  https://doi.org/10.1038/nrneurol.2011.110.CrossRefPubMedGoogle Scholar
  2. 2.
    Pollack, I. F. (1994). Brain tumors in children. New England Journal of Medicine, 331(22), 1500–1507.  https://doi.org/10.1056/nejm199412013312207.CrossRefPubMedGoogle Scholar
  3. 3.
    Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA: a Cancer Journal for Clinicians, 69(1), 7–34.  https://doi.org/10.3322/caac.21551.CrossRefGoogle Scholar
  4. 4.
    Smith, M. A., & Reaman, G. H. (2015). Remaining challenges in childhood cancer and newer targeted therapeutics. Pediatric Clinics of North America, 62(1), 301–312.  https://doi.org/10.1016/j.pcl.2014.09.018.CrossRefPubMedGoogle Scholar
  5. 5.
    Jones, D. T. W., Kieran, M. W., Bouffet, E., Alexandrescu, S., Bandopadhayay, P., Bornhorst, M., et al. (2018). Pediatric low-grade gliomas: next biologically driven steps. Neuro-Oncology, 20(2), 160–173.  https://doi.org/10.1093/neuonc/nox141.CrossRefPubMedGoogle Scholar
  6. 6.
    Aldape, K., Brindle, K. M., Chesler, L., Chopra, R., Gajjar, A., Gilbert, M. R., et al. (2019). Challenges to curing primary brain tumours. Nature Reviews Clinical Oncology, 16(8), 509–520.  https://doi.org/10.1038/s41571-019-0177-5.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mackay, A., Burford, A., Carvalho, D., Izquierdo, E., Fazal-Salom, J., Taylor, K. R., et al. (2017). Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell, 32(4), 520–537.e525.  https://doi.org/10.1016/j.ccell.2017.08.017.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Quail, D. F., & Joyce, J. A. (2017). The microenvironmental landscape of brain tumors. Cancer Cell, 31(3), 326–341.  https://doi.org/10.1016/j.ccell.2017.02.009.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gilbertson, R. J. (2011). Mapping cancer origins. Cell, 145(1), 25–29.  https://doi.org/10.1016/j.cell.2011.03.019.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Abou-Antoun, T. J., Hale, J. S., Lathia, J. D., & Dombrowski, S. M. (2017). Brain cancer stem cells in adults and children: cell biology and therapeutic implications. Neurotherapeutics, 14(2), 372–384.  https://doi.org/10.1007/s13311-017-0524-0.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bahmad, H. F., Chamaa, F., Assi, S., Chalhoub, R. M., Abou-Antoun, T., & Abou-Kheir, W. (2019). Cancer stem cells in neuroblastoma: expanding the therapeutic frontier. Frontiers in Molecular Neuroscience, 12, 131.  https://doi.org/10.3389/fnmol.2019.00131.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bahmad, H. F., & Poppiti, R. J. (submitted). Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets. Journal of Clinical Pathology.Google Scholar
  13. 13.
    Lathia, J. D. (2013). Cancer stem cells: moving past the controversy. CNS Oncol, 2(6), 465–467.  https://doi.org/10.2217/cns.13.42.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Nowak-Sliwinska, P., Scapozza, L., & Altaba, A. R. I. (2019). Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer. Biochimica et biophysica acta. Reviews on cancer, 1871(2), 434–454,  https://doi.org/10.1016/j.bbcan.2019.04.005.CrossRefGoogle Scholar
  15. 15.
    Hernandez, J. J., Pryszlak, M., Smith, L., Yanchus, C., Kurji, N., Shahani, V. M., et al. (2017). Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as Cancer therapeutics. Frontiers in Oncology, 7, 273.  https://doi.org/10.3389/fonc.2017.00273.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bhat-Nakshatri, P., Goswami, C. P., Badve, S., Sledge Jr., G. W., & Nakshatri, H. (2013). Identification of FDA-approved drugs targeting breast cancer stem cells along with biomarkers of sensitivity. Scientific Reports, 3, 2530.  https://doi.org/10.1038/srep02530.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tan, S. K., Jermakowicz, A., Mookhtiar, A. K., Nemeroff, C. B., Schürer, S. C., & Ayad, N. G. (2018). Drug repositioning in glioblastoma: a pathway perspective. [review]. Front Pharmacol, 9(218).  https://doi.org/10.3389/fphar.2018.00218.
  18. 18.
    Pui, C.-H., Gajjar, A. J., Kane, J. R., Qaddoumi, I. A., & Pappo, A. S. (2011). Challenging issues in pediatric oncology. Nature Reviews Clinical Oncology, 8(9), 540–549.  https://doi.org/10.1038/nrclinonc.2011.95.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    National Cancer Institute. (2010). Surveillance, epidemiology and end results (pp. 1975–2007). SEER Cancer Statistics Review: Previous Version http://seer.cancer.gov/csr/.Google Scholar
  20. 20.
    Corsello, S. M., Bittker, J. A., Liu, Z., Gould, J., McCarren, P., Hirschman, J. E., et al. (2017). The drug repurposing hub: a next-generation drug library and information resource. Nature Medicine, 23(4), 405–408.  https://doi.org/10.1038/nm.4306.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Minturn, J. E., & Fisher, M. J. (2013). Gliomas in children. Current Treatment Options in Neurology, 15(3), 316–327.  https://doi.org/10.1007/s11940-013-0225-x.CrossRefPubMedGoogle Scholar
  22. 22.
    Sievert, A. J., & Fisher, M. J. (2009). Pediatric low-grade gliomas. Journal of Child Neurology, 24(11), 1397–1408.  https://doi.org/10.1177/0883073809342005.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    El-Ayadi, M., Ansari, M., Sturm, D., Gielen, G. H., Warmuth-Metz, M., Kramm, C. M., et al. (2017). High-grade glioma in very young children: a rare and particular patient population. Oncotarget, 8(38), 64564–64578.  https://doi.org/10.18632/oncotarget.18478.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sturm, D., Pfister, S. M., & Jones, D. T. W. (2017). Pediatric gliomas: current concepts on diagnosis, biology, and clinical management. Journal of Clinical Oncology, 35(21), 2370–2377.  https://doi.org/10.1200/JCO.2017.73.0242.CrossRefPubMedGoogle Scholar
  25. 25.
    Miyashita, K., Kawakami, K., Nakada, M., Mai, W., Shakoori, A., Fujisawa, H., et al. (2009). Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma. Clinical Cancer Research, 15(3), 887–897.  https://doi.org/10.1158/1078-0432.CCR-08-0760.CrossRefPubMedGoogle Scholar
  26. 26.
    Nam, J. Y., & de Groot, J. F. (2017). Treatment of glioblastoma. Journal of Oncology Practice/ American Society of Clinical Oncology, 13(10), 629–638.  https://doi.org/10.1200/JOP.2017.025536.CrossRefGoogle Scholar
  27. 27.
    Xu, H. S., Qin, X. L., Zong, H. L., He, X. G., & Cao, L. (2017). Cancer stem cell markers in glioblastoma—an update. European Review for Medical and Pharmacological Sciences, 21(14), 3207–3211.PubMedGoogle Scholar
  28. 28.
    Singh, S. K., Clarke, I. D., Hide, T., & Dirks, P. B. (2004). Cancer stem cells in nervous system tumors. Oncogene, 23(43), 7267–7273.  https://doi.org/10.1038/sj.onc.1207946.CrossRefPubMedGoogle Scholar
  29. 29.
    Abbruzzese, C., Matteoni, S., Signore, M., Cardone, L., Nath, K., Glickson, J. D., et al. (2017). Drug repurposing for the treatment of glioblastoma multiforme. Journal of Experimental & Clinical Cancer Research, 36(1), 169.  https://doi.org/10.1186/s13046-017-0642-x.CrossRefGoogle Scholar
  30. 30.
    Wang, Y., Meng, Y., Zhang, S., Wu, H., Yang, D., Nie, C., et al. (2018). Phenformin and metformin inhibit growth and migration of LN229 glioma cells in vitro and in vivo. Onco Targets Ther, 11, 6039–6048.  https://doi.org/10.2147/OTT.S168981.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jiang, W., Finniss, S., Cazacu, S., Xiang, C., Brodie, Z., Mikkelsen, T., et al. (2016). Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma. Oncotarget, 7(35), 56456–56470.  https://doi.org/10.18632/oncotarget.10919.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Koyuturk, M., Ersoz, M., & Altiok, N. (2004). Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase. Neuroscience Letters, 370(2–3), 212–217.  https://doi.org/10.1016/j.neulet.2004.08.020.CrossRefPubMedGoogle Scholar
  33. 33.
    Xiao, A., Brenneman, B., Floyd, D., Comeau, L., Spurio, K., Olmez, I., et al. (2019). Statins affect human glioblastoma and other cancers through TGF-beta inhibition. Oncotarget, 10(18), 1716–1728.  https://doi.org/10.18632/oncotarget.26733.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pinter, M., & Jain, R. K. (2017). Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy. Science Translational Medicine, 9(410).  https://doi.org/10.1126/scitranslmed.aan5616.CrossRefGoogle Scholar
  35. 35.
    Kitabayashi, T., Dong, Y., Furuta, T., Sabit, H., Jiapaer, S., Zhang, J., et al. (2019). Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma. Scientific Reports, 9(1), 10049.  https://doi.org/10.1038/s41598-019-46454-8.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Handley, M. V. (2015). GSK-3 inhibitors in glioblastoma therapy: mechanisms of action. BOSTON UNIVERSITY.Google Scholar
  37. 37.
    Nowicki, M. O., Dmitrieva, N., Stein, A. M., Cutter, J. L., Godlewski, J., Saeki, Y., et al. (2008). Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3. Neuro-Oncology, 10(5), 690–699.  https://doi.org/10.1215/15228517-2008-041.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Chirasani, S. R., Leukel, P., Gottfried, E., Hochrein, J., Stadler, K., Neumann, B., et al. (2013). Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. International Journal of Cancer, 132(4), 843–853.  https://doi.org/10.1002/ijc.27712.CrossRefPubMedGoogle Scholar
  39. 39.
    Leidgens, V., Seliger, C., Jachnik, B., Welz, T., Leukel, P., Vollmann-Zwerenz, A., et al. (2015). Ibuprofen and diclofenac restrict migration and proliferation of human glioma cells by distinct molecular mechanisms. PLoS One, 10(10), e0140613.  https://doi.org/10.1371/journal.pone.0140613.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Tuettenberg, J., Grobholz, R., Korn, T., Wenz, F., Erber, R., & Vajkoczy, P. (2005). Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. Journal of Cancer Research and Clinical Oncology, 131(1), 31–40.  https://doi.org/10.1007/s00432-004-0620-5.CrossRefPubMedGoogle Scholar
  41. 41.
    Johannessen, T. C., Hasan-Olive, M. M., Zhu, H., Denisova, O., Grudic, A., Latif, M. A., et al. (2019). Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide. International Journal of Cancer, 144(7), 1735–1745.  https://doi.org/10.1002/ijc.31912.CrossRefPubMedGoogle Scholar
  42. 42.
    Kang, S., Lee, J. M., Jeon, B., Elkamhawy, A., Paik, S., Hong, J., et al. (2018). Repositioning of the antipsychotic trifluoperazine: synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents. European Journal of Medicinal Chemistry, 151, 186–198.  https://doi.org/10.1016/j.ejmech.2018.03.055.CrossRefPubMedGoogle Scholar
  43. 43.
    Hayashi, K., Michiue, H., Yamada, H., Takata, K., Nakayama, H., Wei, F. Y., et al. (2016). Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. Scientific Reports, 6, 23372.  https://doi.org/10.1038/srep23372.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Al Hassan, M., Fakhoury, I., El Masri, Z., Ghazale, N., Dennaoui, R., El Atat, O., et al. (2018). Metformin treatment inhibits motility and invasion of glioblastoma cancer cells. Analytical Cellular Pathology, 2018, 9.  https://doi.org/10.1155/2018/5917470.CrossRefGoogle Scholar
  45. 45.
    Oesterle, A., Laufs, U., & Liao, J. K. (2017). Pleiotropic effects of statins on the cardiovascular system. Circulation Research, 120(1), 229–243.  https://doi.org/10.1161/CIRCRESAHA.116.308537.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Shojaei, S., Alizadeh, J., Thliveris, J., Koleini, N., Kardami, E., Hatch, G. M., et al. (2018). Statins: a new approach to combat temozolomide chemoresistance in glioblastoma. Journal of Investigative Medicine, 66(8), 1083–1087.  https://doi.org/10.1136/jim-2018-000874.CrossRefPubMedGoogle Scholar
  47. 47.
    Rasmussen, E. R., Pottegard, A., Bygum, A., von Buchwald, C., Homoe, P., & Hallas, J. (2019). Angiotensin II receptor blockers are safe in patients with prior angioedema related to angiotensin-converting enzyme inhibitors - a nationwide registry-based cohort study. Journal of Internal Medicine, 285(5), 553–561.  https://doi.org/10.1111/joim.12867.CrossRefPubMedGoogle Scholar
  48. 48.
    Barreras, A., & Gurk-Turner, C. (2003). Angiotensin II receptor blockers. Proc (Bayl Univ Med Cent), 16(1), 123–126.  https://doi.org/10.1080/08998280.2003.11927893.CrossRefGoogle Scholar
  49. 49.
    Ino, K., Shibata, K., Kajiyama, H., Yamamoto, E., Nagasaka, T., Nawa, A., et al. (2006). Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival. British Journal of Cancer, 94(4), 552–560.  https://doi.org/10.1038/sj.bjc.6602961.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Arrieta, O., Villarreal-Garza, C., Vizcaino, G., Pineda, B., Hernandez-Pedro, N., Guevara-Salazar, P., et al. (2015). Association between AT1 and AT2 angiotensin II receptor expression with cell proliferation and angiogenesis in operable breast cancer. Tumour Biology, 36(7), 5627–5634.  https://doi.org/10.1007/s13277-015-3235-3.CrossRefPubMedGoogle Scholar
  51. 51.
    Rocken, C., Rohl, F. W., Diebler, E., Lendeckel, U., Pross, M., Carl-McGrath, S., et al. (2007). The angiotensin II/angiotensin II receptor system correlates with nodal spread in intestinal type gastric cancer. Cancer Epidemiology, Biomarkers & Prevention, 16(6), 1206–1212.  https://doi.org/10.1158/1055-9965.epi-05-0934.CrossRefGoogle Scholar
  52. 52.
    Feng, E., Sui, C., Wang, T., & Sun, G. (2017). Temozolomide with or without radiotherapy in patients with newly diagnosed glioblastoma Multiforme: a meta-analysis. European Neurology, 77(3–4), 201–210.  https://doi.org/10.1159/000455842.CrossRefPubMedGoogle Scholar
  53. 53.
    Ghaffari, S. (2011). Cancer, stem cells and cancer stem cells: old ideas, new developments. F1000 Med Rep, 3, 23.  https://doi.org/10.3410/M3-23.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Nakada M., M. T, Pyko I., Hayashi Y. and Hamada J. (2011). The pivotal roles of GSK3β in glioma biology In M. Garami (Ed.), Molecular Targets of CNS Tumors IntechOpen.Google Scholar
  55. 55.
    Vashishtha, V., Jinghan, N., & A, K. Y. (2018). Antagonistic role of GSK3 isoforms in glioma survival. Journal of Cancer, 9(10), 1846–1855.  https://doi.org/10.7150/jca.21248.CrossRefGoogle Scholar
  56. 56.
    Llorens-Martin, M., Jurado, J., Hernandez, F., & Avila, J. (2014). GSK-3beta, a pivotal kinase in Alzheimer disease. Frontiers in Molecular Neuroscience, 7, 46.  https://doi.org/10.3389/fnmol.2014.00046.CrossRefPubMedGoogle Scholar
  57. 57.
    del Ser, T., Steinwachs, K. C., Gertz, H. J., Andres, M. V., Gomez-Carrillo, B., Medina, M., et al. (2013). Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. Journal of Alzheimer's Disease, 33(1), 205–215.  https://doi.org/10.3233/JAD-2012-120805.CrossRefPubMedGoogle Scholar
  58. 58.
    Tolosa, E., Litvan, I., Hoglinger, G. U., Burn, D., Lees, A., Andres, M. V., et al. (2014). A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Movement Disorders, 29(4), 470–478.  https://doi.org/10.1002/mds.25824.CrossRefPubMedGoogle Scholar
  59. 59.
    Lovestone, S., Boada, M., Dubois, B., Hull, M., Rinne, J. O., Huppertz, H. J., et al. (2015). A phase II trial of tideglusib in Alzheimer’s disease. Journal of Alzheimer's Disease, 45(1), 75–88.  https://doi.org/10.3233/jad-141959.CrossRefPubMedGoogle Scholar
  60. 60.
    Mathuram, T. L., Ravikumar, V., Reece, L. M., Karthik, S., Sasikumar, C. S., & Cherian, K. M. (2016). Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G0/G1 accumulation and ROS generation. Environmental Toxicology and Pharmacology, 46, 194–205.  https://doi.org/10.1016/j.etap.2016.07.013.CrossRefPubMedGoogle Scholar
  61. 61.
    Zhou, A., Lin, K., Zhang, S., Chen, Y., Zhang, N., Xue, J., et al. (2016). Nuclear GSK3beta promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nature Cell Biology, 18(9), 954–966.  https://doi.org/10.1038/ncb3396.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Chalhoub, R. M., Bahmad, H. F., Harati, H., Assi, S., Araji, T., Bou-Gharios, J., et al. (2019). Specific inhibition of GSK-3β by Tideglusib: potential therapeutic target for neuroblastoma cancer stem cells. Submitted.Google Scholar
  63. 63.
    Hata, A. N., & Breyer, R. M. (2004). Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacology & Therapeutics, 103(2), 147–166.  https://doi.org/10.1016/j.pharmthera.2004.06.003.CrossRefGoogle Scholar
  64. 64.
    Amano, H., Hayashi, I., Endo, H., Kitasato, H., Yamashina, S., Maruyama, T., et al. (2003). Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. The Journal of Experimental Medicine, 197(2), 221–232.  https://doi.org/10.1084/jem.20021408.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Seliger, C., & Hau, P. (2018). Drug repurposing of metabolic agents in malignant glioma. International Journal of Molecular Sciences, 19(9).  https://doi.org/10.3390/ijms19092768.CrossRefGoogle Scholar
  66. 66.
    Li, J., Kim, S. G., & Blenis, J. (2014). Rapamycin: One drug, many effects. Cell Metabolism, 19(3), 373–379.  https://doi.org/10.1016/j.cmet.2014.01.001.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Yang, Z., Hackshaw, A., Feng, Q., Fu, X., Zhang, Y., Mao, C., et al. (2017). Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: a meta-analysis. International Journal of Cancer, 140(12), 2805–2819.  https://doi.org/10.1002/ijc.30691.CrossRefPubMedGoogle Scholar
  68. 68.
    Yalon, M., Rood, B., MacDonald, T. J., McCowage, G., Kane, R., Constantini, S., et al. (2013). A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low-grade glioma (LGG). Pediatric Blood & Cancer, 60(1), 71–76.  https://doi.org/10.1002/pbc.24142.CrossRefGoogle Scholar
  69. 69.
    Mollashahi, B., Aghamaleki, F. S., & Movafagh, A. (2019). The roles of miRNAs in medulloblastoma: a systematic review. J Cancer Prev, 24(2), 79–90.  https://doi.org/10.15430/jcp.2019.24.2.79.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Zulch, K. J. (1980). Principles of the new World Health Organization (WHO) classification of brain tumors. Neuroradiology, 19(2), 59–66.  https://doi.org/10.1007/bf00342596.CrossRefPubMedGoogle Scholar
  71. 71.
    DeAngelis, L. M. (2001). Brain tumors. The New England Journal of Medicine, 344(2), 114–123.  https://doi.org/10.1056/nejm200101113440207.CrossRefPubMedGoogle Scholar
  72. 72.
    Pomeroy, S. L., Tamayo, P., Gaasenbeek, M., Sturla, L. M., Angelo, M., McLaughlin, M. E., et al. (2002). Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature, 415(6870), 436–442.  https://doi.org/10.1038/415436a.CrossRefPubMedGoogle Scholar
  73. 73.
    Thompson, M. C., Fuller, C., Hogg, T. L., Dalton, J., Finkelstein, D., Lau, C. C., et al. (2006). Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. Journal of Clinical Oncology, 24(12), 1924–1931.  https://doi.org/10.1200/jco.2005.04.4974.CrossRefPubMedGoogle Scholar
  74. 74.
    Kool, M., Koster, J., Bunt, J., Hasselt, N. E., Lakeman, A., van Sluis, P., et al. (2008). Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One, 3(8), e3088.  https://doi.org/10.1371/journal.pone.0003088.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Cho, Y. J., Tsherniak, A., Tamayo, P., Santagata, S., Ligon, A., Greulich, H., et al. (2011). Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. Journal of Clinical Oncology, 29(11), 1424–1430.  https://doi.org/10.1200/jco.2010.28.5148.CrossRefPubMedGoogle Scholar
  76. 76.
    Taylor, M. D., Northcott, P. A., Korshunov, A., Remke, M., Cho, Y. J., Clifford, S. C., et al. (2012). Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathologica, 123(4), 465–472.  https://doi.org/10.1007/s00401-011-0922-z.CrossRefPubMedGoogle Scholar
  77. 77.
    Thomas, A., & Noel, G. (2019). Medulloblastoma: optimizing care with a multidisciplinary approach. Journal of Multidisciplinary Healthcare, 12, 335–347.  https://doi.org/10.2147/jmdh.s167808.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Bao, S., Wu, Q., McLendon, R. E., Hao, Y., Shi, Q., Hjelmeland, A. B., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444(7120), 756–760.  https://doi.org/10.1038/nature05236.CrossRefPubMedGoogle Scholar
  79. 79.
    Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., et al. (2004). Identification of human brain tumour initiating cells. Nature, 432(7015), 396–401.  https://doi.org/10.1038/nature03128.CrossRefPubMedGoogle Scholar
  80. 80.
    Abouantoun, T. J., Castellino, R. C., & MacDonald, T. J. (2011). Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells. Journal of Neuro-Oncology, 101(2), 215–226.  https://doi.org/10.1007/s11060-010-0259-9.CrossRefPubMedGoogle Scholar
  81. 81.
    Abouantoun, T. J., & MacDonald, T. J. (2009). Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor. Molecular Cancer Therapeutics, 8(5), 1137–1147.  https://doi.org/10.1158/1535-7163.mct-08-0889.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Wolle, D., Lee, S. J., Li, Z., Litan, A., Barwe, S. P., & Langhans, S. A. (2014). Inhibition of epidermal growth factor signaling by the cardiac glycoside ouabain in medulloblastoma. Cancer Medicine, 3(5), 1146–1158.  https://doi.org/10.1002/cam4.314.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Huang, L., Garrett Injac, S., Cui, K., Braun, F., Lin, Q., Du, Y., et al. (2018). Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma. Science Translational Medicine, 10(464).  https://doi.org/10.1126/scitranslmed.aat0150.CrossRefGoogle Scholar
  84. 84.
    Takwi, A. A., Li, Y., Becker Buscaglia, L. E., Zhang, J., Choudhury, S., Park, A. K., et al. (2012). A statin-regulated microRNA represses human c-Myc expression and function. EMBO Molecular Medicine, 4(9), 896–909.  https://doi.org/10.1002/emmm.201101045.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Bar, E. E., Chaudhry, A., Farah, M. H., & Eberhart, C. G. (2007). Hedgehog signaling promotes medulloblastoma survival via Bc/II. The American Journal of Pathology, 170(1), 347–355.  https://doi.org/10.2353/ajpath.2007.060066.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Bar, E. E., & Stearns, D. (2008). New developments in medulloblastoma treatment: the potential of a cyclopamine-lovastatin combination. Expert Opinion on Investigational Drugs, 17(2), 185–195.  https://doi.org/10.1517/13543784.17.2.185.CrossRefPubMedGoogle Scholar
  87. 87.
    Sheikholeslami, K., Ali Sher, A., Lockman, S., Kroft, D., Ganjibakhsh, M., Nejati-Koshki, K., et al. (2019). Simvastatin induces apoptosis in medulloblastoma brain tumor cells via mevalonate cascade prenylation substrates. Cancers (Basel), 11(7).  https://doi.org/10.3390/cancers11070994.CrossRefGoogle Scholar
  88. 88.
    Bai, R. Y., Staedtke, V., Rudin, C. M., Bunz, F., & Riggins, G. J. (2015). Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis. Neuro-Oncology, 17(4), 545–554.  https://doi.org/10.1093/neuonc/nou234.CrossRefPubMedGoogle Scholar
  89. 89.
    Larsen, A. R., Bai, R. Y., Chung, J. H., Borodovsky, A., Rudin, C. M., Riggins, G. J., et al. (2015). Repurposing the antihelmintic mebendazole as a hedgehog inhibitor. Molecular Cancer Therapeutics, 14(1), 3–13.  https://doi.org/10.1158/1535-7163.mct-14-0755-t.CrossRefPubMedGoogle Scholar
  90. 90.
    Bell, J. B., Rink, J. S., Eckerdt, F., Clymer, J., Goldman, S., Thaxton, C. S., et al. (2018). HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma. Scientific Reports, 8(1), 1211.  https://doi.org/10.1038/s41598-017-18100-8.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Rossi, A., Russo, G., Puca, A., La Montagna, R., Caputo, M., Mattioli, E., et al. (2009). The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells. International Journal of Cancer, 125(1), 235–243.  https://doi.org/10.1002/ijc.24331.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Baryawno, N., Sveinbjornsson, B., Eksborg, S., Orrego, A., Segerstrom, L., Oqvist, C. O., et al. (2008). Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets. Neuro-Oncology, 10(5), 661–674.  https://doi.org/10.1215/15228517-2008-035.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Yang, M. Y., Lee, H. T., Chen, C. M., Shen, C. C., & Ma, H. I. (2014). Celecoxib suppresses the phosphorylation of STAT3 protein and can enhance the radiosensitivity of medulloblastoma-derived cancer stem-like cells. International Journal of Molecular Sciences, 15(6), 11013–11029.  https://doi.org/10.3390/ijms150611013.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Eslin, D., Lee, C., Sankpal, U. T., Maliakal, P., Sutphin, R. M., Abraham, L., et al. (2013). Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study. Tumour Biology, 34(5), 2781–2789.  https://doi.org/10.1007/s13277-013-0836-6.CrossRefPubMedGoogle Scholar
  95. 95.
    Kaplan, J. H. (2002). Biochemistry of Na,K-ATPase. Annual Review of Biochemistry, 71, 511–535.  https://doi.org/10.1146/annurev.biochem.71.102201.141218.CrossRefPubMedGoogle Scholar
  96. 96.
    Lingrel, J. B. (2010). The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annual Review of Physiology, 72, 395–412.  https://doi.org/10.1146/annurev-physiol-021909-135725.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Mijatovic, T., Van Quaquebeke, E., Delest, B., Debeir, O., Darro, F., & Kiss, R. (2007). Cardiotonic steroids on the road to anti-cancer therapy. Biochimica et Biophysica Acta, 1776(1), 32–57.  https://doi.org/10.1016/j.bbcan.2007.06.002.CrossRefPubMedGoogle Scholar
  98. 98.
    Yamada, M., Ikeuchi, T., & Hatanaka, H. (1997). The neurotrophic action and signalling of epidermal growth factor. Progress in Neurobiology, 51(1), 19–37.CrossRefGoogle Scholar
  99. 99.
    Wong, R. W., & Guillaud, L. (2004). The role of epidermal growth factor and its receptors in mammalian CNS. Cytokine & Growth Factor Reviews, 15(2–3), 147–156.  https://doi.org/10.1016/j.cytogfr.2004.01.004.CrossRefGoogle Scholar
  100. 100.
    Gilbertson, R. J., Perry, R. H., Kelly, P. J., Pearson, A. D., & Lunec, J. (1997). Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Research, 57(15), 3272–3280.PubMedGoogle Scholar
  101. 101.
    Waage, I. S., Vreim, I., & Torp, S. H. (2013). C-erbB2/HER2 in human gliomas, medulloblastomas, and meningiomas: a minireview. International Journal of Surgical Pathology, 21(6), 573–582.  https://doi.org/10.1177/1066896913492196.CrossRefPubMedGoogle Scholar
  102. 102.
    Bal, M. M., Das Radotra, B., Srinivasan, R., & Sharma, S. C. (2006). Does c-erbB-2 expression have a role in medulloblastoma prognosis? Indian Journal of Pathology & Microbiology, 49(4), 535–539.Google Scholar
  103. 103.
    Ivanov, D. P., Coyle, B., Walker, D. A., & Grabowska, A. M. (2016). In vitro models of medulloblastoma: choosing the right tool for the job. Journal of Biotechnology, 236, 10–25.  https://doi.org/10.1016/j.jbiotec.2016.07.028.CrossRefPubMedGoogle Scholar
  104. 104.
    Zeki, A. A., Yeganeh, B., Kenyon, N. J., & Ghavami, S. (2017). Editorial: new insights into a classical pathway: key roles of the mevalonate cascade in different diseases (part II). Current Molecular Pharmacology, 10(2), 74–76.  https://doi.org/10.2174/187446721002170301204357.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Matusewicz, L., Meissner, J., Toporkiewicz, M., & Sikorski, A. F. (2015). The effect of statins on cancer cells—review. Tumour Biology, 36(7), 4889–4904.  https://doi.org/10.1007/s13277-015-3551-7.CrossRefPubMedGoogle Scholar
  106. 106.
    Chan, K. K., Oza, A. M., & Siu, L. L. (2003). The statins as anticancer agents. Clinical Cancer Research, 9(1), 10–19.PubMedGoogle Scholar
  107. 107.
    Bjarnadottir, O., Kimbung, S., Johansson, I., Veerla, S., Jonsson, M., Bendahl, P. O., et al. (2015). Global transcriptional changes following statin treatment in breast cancer. Clinical Cancer Research, 21(15), 3402–3411.  https://doi.org/10.1158/1078-0432.ccr-14-1403.CrossRefPubMedGoogle Scholar
  108. 108.
    Wang, T., Seah, S., Loh, X., Chan, C. W., Hartman, M., Goh, B. C., et al. (2016). Simvastatin-induced breast cancer cell death and deactivation of PI3K/Akt and MAPK/ERK signalling are reversed by metabolic products of the mevalonate pathway. Oncotarget, 7(3), 2532–2544.  https://doi.org/10.18632/oncotarget.6304.CrossRefPubMedGoogle Scholar
  109. 109.
    de Bont, J. M., Packer, R. J., Michiels, E. M., den Boer, M. L., & Pieters, R. (2008). Biological background of pediatric medulloblastoma and ependymoma: a review from a translational research perspective. Neuro-Oncology, 10(6), 1040–1060.  https://doi.org/10.1215/15228517-2008-059.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Cochrane, C. R., Szczepny, A., Watkins, D. N., & Cain, J. E. (2015). Hedgehog signaling in the maintenance of cancer stem cells. Cancers (Basel), 7(3), 1554–1585.  https://doi.org/10.3390/cancers7030851.CrossRefGoogle Scholar
  111. 111.
    Northcott, P. A., Dubuc, A. M., Pfister, S., & Taylor, M. D. (2012). Molecular subgroups of medulloblastoma. Expert Review of Neurotherapeutics, 12(7), 871–884.  https://doi.org/10.1586/ern.12.66.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Guerini, A. E., Triggiani, L., Maddalo, M., Bonu, M. L., Frassine, F., Baiguini, A., et al. (2019). Mebendazole as a candidate for drug repurposing in oncology: an extensive review of current literature. Cancers (Basel), 11(9).  https://doi.org/10.3390/cancers11091284.CrossRefGoogle Scholar
  113. 113.
    Kohler, P. (2001). The biochemical basis of anthelmintic action and resistance. International Journal for Parasitology, 31(4), 336–345.  https://doi.org/10.1016/s0020-7519(01)00131-x.CrossRefPubMedGoogle Scholar
  114. 114.
    Goel, H. L., & Mercurio, A. M. (2013). VEGF targets the tumour cell. Nature Reviews. Cancer, 13(12), 871–882.  https://doi.org/10.1038/nrc3627.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Bai, R. Y., Staedtke, V., Wanjiku, T., Rudek, M. A., Joshi, A., Gallia, G. L., et al. (2015). Brain penetration and efficacy of different mebendazole polymorphs in a mouse brain tumor model. Clinical Cancer Research, 21(15), 3462–3470.  https://doi.org/10.1158/1078-0432.ccr-14-2681.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Rohatgi, R., Milenkovic, L., & Scott, M. P. (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science, 317(5836), 372–376.  https://doi.org/10.1126/science.1139740.CrossRefPubMedGoogle Scholar
  117. 117.
    Yuen, G. J., Weller, S., & Pakes, G. E. (2008). A review of the pharmacokinetics of abacavir. Clinical Pharmacokinetics, 47(6), 351–371.  https://doi.org/10.2165/00003088-200847060-00001.CrossRefPubMedGoogle Scholar
  118. 118.
    Phatak, P., & Burger, A. M. (2007). Telomerase and its potential for therapeutic intervention. British Journal of Pharmacology, 152(7), 1003–1011.  https://doi.org/10.1038/sj.bjp.0707374.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Tendian, S. W., & Parker, W. B. (2000). Interaction of deoxyguanosine nucleotide analogs with human telomerase. Molecular Pharmacology, 57(4), 695–699.  https://doi.org/10.1124/mol.57.4.695.CrossRefPubMedGoogle Scholar
  120. 120.
    Shay, J. W., & Keith, W. N. (2008). Targeting telomerase for cancer therapeutics. British Journal of Cancer, 98(4), 677–683.  https://doi.org/10.1038/sj.bjc.6604209.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Chang, Q., Pang, J. C., Li, J., Hu, L., Kong, X., & Ng, H. K. (2004). Molecular analysis of PinX1 in medulloblastomas. International Journal of Cancer, 109(2), 309–314.  https://doi.org/10.1002/ijc.11689.CrossRefPubMedGoogle Scholar
  122. 122.
    Witzig, T. E., Timm, M., Stenson, M., Svingen, P. A., & Kaufmann, S. H. (2000). Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in combination with chemotherapeutic agents. Clinical Cancer Research, 6(2), 681–692.PubMedGoogle Scholar
  123. 123.
    Shay, J. W., & Wright, W. E. (2005). Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis, 26(5), 867–874.  https://doi.org/10.1093/carcin/bgh296.CrossRefPubMedGoogle Scholar
  124. 124.
    Epling-Burnette, P. K., Liu, J. H., Catlett-Falcone, R., Turkson, J., Oshiro, M., Kothapalli, R., et al. (2001). Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. The Journal of Clinical Investigation, 107(3), 351–362.  https://doi.org/10.1172/jci9940.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Kim, K. W., Mutter, R. W., Cao, C., Albert, J. M., Shinohara, E. T., Sekhar, K. R., et al. (2006). Inhibition of signal transducer and activator of transcription 3 activity results in down-regulation of Survivin following irradiation. Molecular Cancer Therapeutics, 5(11), 2659–2665.  https://doi.org/10.1158/1535-7163.mct-06-0261.CrossRefPubMedGoogle Scholar
  126. 126.
    Chen, K. H., Hsu, C. C., Song, W. S., Huang, C. S., Tsai, C. C., Kuo, C. D., et al. (2010). Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells. Child's Nervous System, 26(11), 1605–1612.  https://doi.org/10.1007/s00381-010-1190-2.CrossRefPubMedGoogle Scholar
  127. 127.
    Abdelrahim, M., Baker, C. H., Abbruzzese, J. L., & Safe, S. (2006). Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. Journal of the National Cancer Institute, 98(12), 855–868.  https://doi.org/10.1093/jnci/djj232.CrossRefPubMedGoogle Scholar
  128. 128.
    Shelake, S., Sankpal, U. T., Paul Bowman, W., Wise, M., Ray, A., & Basha, R. (2017). Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth. Investigational New Drugs, 35(2), 158–165.  https://doi.org/10.1007/s10637-016-0417-9.CrossRefPubMedGoogle Scholar
  129. 129.
    Yao, J. C., Wang, L., Wei, D., Gong, W., Hassan, M., Wu, T. T., et al. (2004). Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clinical Cancer Research, 10(12 Pt 1), 4109–4117.  https://doi.org/10.1158/1078-0432.ccr-03-0628.CrossRefPubMedGoogle Scholar
  130. 130.
    Patil, S., Sankpal, U. T., Hurtado, M., Bowman, W. P., Murray, J., Borgmann, K., et al. (2019). Combination of clotam and vincristine enhances anti-proliferative effect in medulloblastoma cells. Gene, 705, 67–76.  https://doi.org/10.1016/j.gene.2019.04.037.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Colon, N. C., & Chung, D. H. (2011). Neuroblastoma. Advances in Pediatrics, 58(1), 297–311.  https://doi.org/10.1016/j.yapd.2011.03.011.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Zaatiti, H., Abdallah, J., Nasr, Z., Khazen, G., Sandler, A., & Abou-Antoun, T. J. (2018). Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration. International Journal of Oncology, 52(3), 787–803.  https://doi.org/10.3892/ijo.2018.4236.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Abou-Antoun, T. J., Nazarian, J., Ghanem, A., Vukmanovic, S., & Sandler, A. D. (2018). Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant properties: a possible explanation for radio-therapy resistance. PLoS One, 13(1), e0189711.  https://doi.org/10.1371/journal.pone.0189711.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Lopez-Barcons, L., Maurer, B. J., Kang, M. H., & Reynolds, C. P. (2017). P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models. International Journal of Cancer, 141(2), 405–413.  https://doi.org/10.1002/ijc.30706.CrossRefPubMedGoogle Scholar
  135. 135.
    Michaelis, M., Agha, B., Rothweiler, F., Löschmann, N., Voges, Y., Mittelbronn, M., et al. (2015). Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen. Scientific Reports, 5, 8202–8202.  https://doi.org/10.1038/srep08202.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Zhong, X., Zhao, E., Tang, C., Zhang, W., Tan, J., Dong, Z., et al. (2016). Antibiotic drug tigecycline reduces neuroblastoma cells proliferation by inhibiting Akt activation in vitro and in vivo. Tumor Biology, 37(6), 7615–7623.  https://doi.org/10.1007/s13277-015-4613-6.CrossRefPubMedGoogle Scholar
  137. 137.
    Di Zanni, E., Bianchi, G., Ravazzolo, R., Raffaghello, L., Ceccherini, I., & Bachetti, T. (2017). Targeting of PHOX2B expression allows the identification of drugs effective in counteracting neuroblastoma cell growth. Oncotarget, 8(42), 72133–72146.  https://doi.org/10.18632/oncotarget.19922.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Aveic, S., Pantile, M., Polo, P., Sidarovich, V., De Mariano, M., Quattrone, A., et al. (2018). Autophagy inhibition improves the cytotoxic effects of receptor tyrosine kinase inhibitors. Cancer Cell International, 18, 63–63.  https://doi.org/10.1186/s12935-018-0557-4.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Saulnier Sholler, G. L., Kalkunte, S., Greenlaw, C., McCarten, K., & Forman, E. (2006). Antitumor activity of Nifurtimox observed in a patient with neuroblastoma. Journal of Pediatric Hematology/Oncology, 28(10).Google Scholar
  140. 140.
    Saulnier Sholler, G. L., Brard, L., Straub, J. A., Dorf, L., Illeyne, S., Koto, K., et al. (2009). Nifurtimox induces apoptosis of neuroblastoma cells in vitro and in vivo. Journal of Pediatric Hematology/Oncology, 31(3), 187–193.  https://doi.org/10.1097/MPH.0b013e3181984d91.CrossRefPubMedGoogle Scholar
  141. 141.
    Cabanillas Stanchi, K. M., Bruchelt, G., Handgretinger, R., & Holzer, U. (2015). Nifurtimox reduces N-Myc expression and aerobic glycolysis in neuroblastoma. Cancer Biology & Therapy, 16(9), 1353–1363.  https://doi.org/10.1080/15384047.2015.1070987.CrossRefGoogle Scholar
  142. 142.
    Kong, E., Zhu, J., Wu, W., Ren, H., Jiao, X., Wang, H., et al. (2019). Nifurtimox inhibits the progression of neuroblastoma in vivo. Journal of Cancer, 10(10), 2194–2204.  https://doi.org/10.7150/jca.27851.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Bassiri, H., Benavides, A., Haber, M., Gilmour, S. K., Norris, M. D., & Hogarty, M. D. (2015). Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. Translational pediatrics, 4(3), 226–238.  https://doi.org/10.3978/j.issn.2224-4336.2015.04.06.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Lozier, A. M., Rich, M. E., Grawe, A. P., Peck, A. S., Zhao, P., Chang, A. T.-T., et al. (2015). Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma. Oncotarget, 6(1), 196–206.  https://doi.org/10.18632/oncotarget.2768.CrossRefPubMedGoogle Scholar
  145. 145.
    Larsson, K., Kock, A., Idborg, H., Arsenian Henriksson, M., Martinsson, T., Johnsen, J. I., et al. (2015). COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset. Proceedings of the National Academy of Sciences of the United States of America, 112(26), 8070–8075.  https://doi.org/10.1073/pnas.1424355112.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Mooney, M. R., Geerts, D., Kort, E. J., & Bachmann, A. S. (2019). Anti-tumor effect of sulfasalazine in neuroblastoma. Biochemical Pharmacology, 162, 237–249.  https://doi.org/10.1016/j.bcp.2019.01.007.CrossRefPubMedGoogle Scholar
  147. 147.
    Komar-Stossel, C., Gross, E., Dery, E., Corchia, N., Meir, K., Fried, I., et al. (2014). TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model—evaluation by MRI. PLoS One, 9(3), e90224–e90224.  https://doi.org/10.1371/journal.pone.0090224.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Campos-Arroyo, D., Maldonado, V., Bahena, I., Quintanar, V., Patiño, N., Carlos Martinez-Lazcano, J., et al. (2016). Probenecid sensitizes neuroblastoma cancer stem cells to cisplatin. Cancer Investigation, 34(3), 155–166.  https://doi.org/10.3109/07357907.2016.1139717.CrossRefPubMedGoogle Scholar
  149. 149.
    Rodríguez-Hernández, C. J., Mateo-Lozano, S., García, M., Casalà, C., Briansó, F., Castrejón, N., et al. (2016). Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens. Oncotarget, 7(13), 16112–16129.  https://doi.org/10.18632/oncotarget.7448.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Nishio, N., Fujita, M., Tanaka, Y., Maki, H., Zhang, R., Hirosawa, T., et al. (2012). Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by human γδ T cells. Journal of Immunotherapy, 35(8).CrossRefGoogle Scholar
  151. 151.
    Alizadeh, J., Zeki, A. A., Mirzaei, N., Tewary, S., Rezaei Moghadam, A., Glogowska, A., et al. (2017). Mevalonate Cascade inhibition by simvastatin induces the intrinsic apoptosis pathway via depletion of isoprenoids in tumor cells. Scientific Reports, 7, 44841–44841.  https://doi.org/10.1038/srep44841.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Su, C., Shi, A., Cao, G., Tao, T., Chen, R., Hu, Z., et al. (2015). Fenofibrate suppressed proliferation and migration of human neuroblastoma cells via oxidative stress dependent of TXNIP upregulation. Biochemical and Biophysical Research Communications, 460(4), 983–988.  https://doi.org/10.1016/j.bbrc.2015.03.138.CrossRefPubMedGoogle Scholar
  153. 153.
    Costa, D., Gigoni, A., Würth, R., Cancedda, R., Florio, T., & Pagano, A. (2014). Metformin inhibition of neuroblastoma cell proliferation is differently modulated by cell differentiation induced by retinoic acid or overexpression of NDM29 non-coding RNA. Cancer Cell International, 14, 59–59.  https://doi.org/10.1186/1475-2867-14-59.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Kumar, A., Al-Sammarraie, N., DiPette, D. J., & Singh, U. S. (2014). Metformin impairs Rho GTPase signaling to induce apoptosis in neuroblastoma cells and inhibits growth of tumors in the xenograft mouse model of neuroblastoma. Oncotarget, 5(22), 11709–11722.  https://doi.org/10.18632/oncotarget.2606.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Vujic, I., Sanlorenzo, M., Posch, C., Esteve-Puig, R., Yen, A. J., Kwong, A., et al. (2015). Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget, 6(2), 969–978.  https://doi.org/10.18632/oncotarget.2824.CrossRefPubMedGoogle Scholar
  156. 156.
    Mouhieddine, T. H., Nokkari, A., Itani, M. M., Chamaa, F., Bahmad, H., Monzer, A., et al. (2015). Metformin and Ara-a effectively suppress brain cancer by targeting cancer stem/progenitor cells. Frontiers in Neuroscience, 9, 442–442.  https://doi.org/10.3389/fnins.2015.00442.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Binlateh, T., Tanasawet, S., Rattanaporn, O., Sukketsiri, W., & Hutamekalin, P. (2019). Metformin promotes neuronal differentiation via crosstalk between Cdk5 and Sox6 in neuroblastoma cells. Evidence-based complementary and alternative medicine : eCAM, 2019, 1765182–1765182.  https://doi.org/10.1155/2019/1765182.CrossRefGoogle Scholar
  158. 158.
    Vella, S., Conaldi, P. G., Florio, T., & Pagano, A. (2016). PPAR gamma in neuroblastoma: the translational perspectives of hypoglycemic drugs. PPAR Research, 2016, 3038164–3038164.  https://doi.org/10.1155/2016/3038164.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Wolter, J. K., Wolter, N. E., Blanch, A., Partridge, T., Cheng, L., Morgenstern, D. A., et al. (2014). Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma. Oncotarget, 5(1), 161–172.  https://doi.org/10.18632/oncotarget.1083.CrossRefPubMedGoogle Scholar
  160. 160.
    Vella, S., Penna, I., Longo, L., Pioggia, G., Garbati, P., Florio, T., et al. (2015). Perhexiline maleate enhances antitumor efficacy of cisplatin in neuroblastoma by inducing over-expression of NDM29 ncRNA. Scientific Reports, 5, 18144–18144.  https://doi.org/10.1038/srep18144.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Gu, S., Tian, Y., Chlenski, A., Salwen, H. R., Lu, Z., Raj, J. U., et al. (2012). Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. Anti-Cancer Drugs, 23(10), 1054–1066.  https://doi.org/10.1097/CAD.0b013e32835739dd.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Shah, R. D., Jagtap, J. C., Mruthyunjaya, S., Shelke, G. V., Pujari, R., Das, G., et al. (2013). Sodium valproate potentiates staurosporine-induced apoptosis in neuroblastoma cells via Akt/survivin independently of HDAC inhibition. Journal of Cellular Biochemistry, 114(4), 854–863.  https://doi.org/10.1002/jcb.24422.CrossRefPubMedGoogle Scholar
  163. 163.
    Groh, T., Hrabeta, J., Ashraf Khalil, M., Doktorova, H., Eckschlager, T., & Stiborova, M. (2015). The synergistic effects of DNA-damaging drugs cisplatin and etoposide with a histone deacetylase inhibitor valproate in high-risk neuroblastoma cells. International Journal of Oncology, 47(1), 343–352.CrossRefGoogle Scholar
  164. 164.
    Fang, E., Wang, J., Hong, M., Zheng, L., & Tong, Q. (2019). Valproic acid suppresses Warburg effect and tumor progression in neuroblastoma. Biochemical and Biophysical Research Communications, 508(1), 9–16.  https://doi.org/10.1016/j.bbrc.2018.11.103.CrossRefPubMedGoogle Scholar
  165. 165.
    Bayat Mokhtari, R., Baluch, N., Ka Hon Tsui, M., Kumar, S., S Homayouni, T., Aitken, K., et al. (2017). Acetazolamide potentiates the anti-tumor potential of HDACi, MS-275, in neuroblastoma. BMC Cancer, 17(1), 156–156,  https://doi.org/10.1186/s12885-017-3126-7.
  166. 166.
    Bilir, A., Erguven, M., Yazihan, N., Aktas, E., Oktem, G., & Sabanci, A. (2010). Enhancement of vinorelbine-induced cytotoxicity and apoptosis by clomipramine and lithium chloride in human neuroblastoma cancer cell line SH-SY5Y. Journal of Neuro-Oncology, 100(3), 385–395.  https://doi.org/10.1007/s11060-010-0209-6.CrossRefPubMedGoogle Scholar
  167. 167.
    Zheng, X., Naiditch, J., Czurylo, M., Jie, C., Lautz, T., Clark, S., et al. (2013). Differential effect of long-term drug selection with doxorubicin and vorinostat on neuroblastoma cells with cancer stem cell characteristics. Cell Death & Disease, 4(7), e740–e740.  https://doi.org/10.1038/cddis.2013.264.CrossRefGoogle Scholar
  168. 168.
    Sidarovich, V., De Mariano, M., Aveic, S., Pancher, M., Adami, V., Gatto, P., et al. (2018). A high-content screening of anticancer compounds suggests the multiple tyrosine kinase inhibitor Ponatinib for repurposing in neuroblastoma therapy. Molecular Cancer Therapeutics, 17(7), 1405–1415.  https://doi.org/10.1158/1535-7163.mct-17-0841.CrossRefPubMedGoogle Scholar
  169. 169.
    Bahmad, H. F., Mouhieddine, T. H., Chalhoub, R. M., Assi, S., Araji, T., Chamaa, F., et al. (2018). The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma. Oncotarget, 9(71), 33549-33561,  https://doi.org/10.18632/oncotarget.26088.
  170. 170.
    Cerna, T., Hrabeta, J., Eckschlager, T., Frei, E., Schmeiser, H. H., Arlt, V. M., et al. (2018). The histone deacetylase inhibitor valproic acid exerts a synergistic cytotoxicity with the DNA-damaging drug Ellipticine in neuroblastoma cells. International Journal of Molecular Sciences, 19(1), 164.  https://doi.org/10.3390/ijms19010164.CrossRefPubMedCentralGoogle Scholar
  171. 171.
    Chen, Y. U. N., Tsai, Y.-H., & Tseng, S.-H. (2011). Combined Valproic acid and celecoxib treatment induced synergistic cytotoxicity and apoptosis in neuroblastoma cells. Anticancer Research, 31(6), 2231–2239.PubMedGoogle Scholar
  172. 172.
    He, W., Wu, Y., Tang, X., Xia, Y., He, G., Min, Z., et al. (2016). HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells. Oncotarget, 7(6), 6727–6747.  https://doi.org/10.18632/oncotarget.6797.CrossRefPubMedGoogle Scholar
  173. 173.
    Dedoni, S., Marras, L., Olianas, M. C., Ingianni, A., & Onali, P. (2019). Downregulation of TrkB expression and signaling by Valproic acid and other histone deacetylase inhibitors. Journal of Pharmacology and Experimental Therapeutics, 370(3), 490.  https://doi.org/10.1124/jpet.119.258129.CrossRefPubMedGoogle Scholar
  174. 174.
    Khalil, M. A., Hraběta, J., Groh, T., Procházka, P., Doktorová, H., & Eckschlager, T. (2016). Valproic acid increases CD133 positive cells that show low sensitivity to cytostatics in neuroblastoma. PLoS One, 11(9), e0162916–e0162916.  https://doi.org/10.1371/journal.pone.0162916.CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Lange, I., Espinoza-Fuenzalida, I., Ali, M. W., Serrano, L. E., & Koomoa, D.-L. T. (2017). FTY-720 induces apoptosis in neuroblastoma via multiple signaling pathways. Oncotarget, 8(66), 109985–109999.  https://doi.org/10.18632/oncotarget.22452.CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Kanno, H., Nishihara, H., Oikawa, M., Ozaki, Y., Murata, J., Sawamura, Y., et al. (2012). Expression of O6-methylguanine DNA methyltransferase (MGMT) and immunohistochemical analysis of 12 pineal parenchymal tumors. Neuropathology, 32(6), 647–653.  https://doi.org/10.1111/j.1440-1789.2012.01315.x.CrossRefPubMedGoogle Scholar
  177. 177.
    DeBoer, R., Batjer, H., Marymont, M., Goldman, S., Walker, M., Gottardi-Littell, N., et al. (2009). Response of an adult patient with pineoblastoma to vorinostat and retinoic acid. Journal of Neuro-Oncology, 95(2), 289–292.  https://doi.org/10.1007/s11060-009-9921-5.CrossRefPubMedGoogle Scholar
  178. 178.
    Mohankumar, K. M., Currle, D. S., White, E., Boulos, N., Dapper, J., Eden, C., et al. (2015). An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes. Nature Genetics, 47(8), 878–887.  https://doi.org/10.1038/ng.3323.CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Nimmervoll, B. V., Boulos, N., Bianski, B., Dapper, J., DeCuypere, M., Shelat, A., et al. (2018). Establishing a preclinical multidisciplinary board for brain tumors. Clinical Cancer Research, 24(7), 1654.  https://doi.org/10.1158/1078-0432.CCR-17-2168.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of MedicineAmerican University of BeirutBeirutLebanon
  2. 2.School of Pharmacy, Department of Pharmaceutical SciencesLebanese American UniversityByblosLebanon

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