Skip to main content
SpringerLink
Log in

Long-term exposure to irinotecan reduces cell migration in glioma cells

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

In spite of considerable research into the therapies for glioblastoma multiforme this tumour type remains very difficult to treat. As well as having a tendency to be inherently resistant to chemotherapy, glioblastoma multiforme also displays local invasion. Cell line studies have a continued and important role to play in understanding the mechanisms associated with both chemotherapy resistance and invasion. In the current study we have utilized the C6 glioma cell line to investigate the response to long-term, clinically relevant application of topoisomerase I and II inhibitors. Treatment with etoposide resulted in an increase in resistance to this topoisomerase II inhibitor. By contrast, the continuous exposure to a topoisomerase I inhibitor did not result in increased drug resistance, but was associated with a reduction in cell migration. This data supports further investigation of topoisomerase I inhibition as a means to inhibit glioma invasion without the development of parallel chemoresistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-Oncol 14(Suppl 5):v1–49. doi:10.1093/neuonc/nos218

    Article  PubMed  PubMed Central  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  3. Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31:4085–4091. doi:10.1200/JCO.2013.49.6968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Haar CP, Hebbar P, Wallace GCt, Das A, Vandergrift WA, 3rd, Smith JA, Giglio P, Patel SJ, Ray SK, Banik NL (2012) Drug resistance in glioblastoma: a mini review. Neurochem Res 37: 1192–1200 doi:10.1007/s11064-011-0701-1

  5. Cuddapah VA, Robel S, Watkins S, Sontheimer H (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15:455–465. doi:10.1038/nrn3765

    Article  CAS  PubMed  Google Scholar 

  6. Paw I, Carpenter RC, Watabe K, Debinski W, Lo HW (2015) Mechanisms regulating glioma invasion. Cancer Lett 362:1–7. doi:10.1016/j.canlet.2015.03.015

    Article  CAS  PubMed  Google Scholar 

  7. Sanai N, Berger MS (2008) Glioma extent of resection and its impact on patient outcome. Neurosurgery 62:753–764. doi:10.1227/01.neu.0000318159.21731.cf

    Article  PubMed  Google Scholar 

  8. Prabhu S, Harris F, Lea R, Snape TJ (2014) Small-molecule clinical trial candidates for the treatment of glioma. Drug Discovery Today 19:1298–1308. doi:10.1016/j.drudis.2014.02.007 discussion 264–756

    Article  CAS  PubMed  Google Scholar 

  9. Chikamori K, Grabowski DR, Kinter M, Willard BB, Yadav S, Aebersold RH, Bukowski RM, Hickson ID, Andersen AH, Ganapathi R, Ganapathi MK (2003) Phosphorylation of serine 1106 in the catalytic domain of topoisomerase II alpha regulates enzymatic activity and drug sensitivity. J Biol Chem 278:12696–12702. doi:10.1074/jbc.M300837200

    Article  CAS  PubMed  Google Scholar 

  10. Adachi N, Suzuki H, Iiizumi S, Koyama H (2003) Hypersensitivity of nonhomologous DNA end-joining mutants to VP-16 and ICRF-193: implications for the repair of topoisomerase II-mediated DNA damage. J Biol Chem 278:35897–35902. doi:10.1074/jbc.M306500200

    Article  CAS  PubMed  Google Scholar 

  11. Benda P, Lightbody J, Sato G, Levine L, Sweet W (1968) Differentiated rat glial cell strain in tissue culture. Science 161:370–371

    Article  CAS  PubMed  Google Scholar 

  12. Schmidek HH, Nielsen SL, Schiller AL, Messer J (1971) Morphological studies of rat brain tumors induced by N-nitrosomethylurea. J Neurosurg 34:335–340. doi:10.3171/jns.1971.34.3.0335

    Article  CAS  PubMed  Google Scholar 

  13. Auer RN, Del Maestro RF, Anderson R (1981) A simple and reproducible experimental in vivo glioma model. Can J Neurol Sci Le J Can des Sci Neurol 8:325–331

    CAS  Google Scholar 

  14. Barth RF, Kaur B (2009) Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J Neurooncol 94:299–312. doi:10.1007/s11060-009-9875-7

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34:1514–1521

    Article  CAS  PubMed  Google Scholar 

  16. Pollack IF, Erff M, Bom D, Burke TG, Strode JT, Curran DP (1999) Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo. Cancer Res 59:4898–4905

    CAS  PubMed  Google Scholar 

  17. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: RESEARCH0034

  18. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C (2006) Clonogenic assay of cells in vitro. Nat Protoc 1:2315–2319. doi:10.1038/nprot.2006.339

    Article  CAS  PubMed  Google Scholar 

  20. Kartner N, Riordan JR, Ling V (1983) Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221:1285–1288

    Article  CAS  PubMed  Google Scholar 

  21. Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev 5:219–234

    CAS  Google Scholar 

  22. Goldwirt L, Beccaria K, Carpentier A, Farinotti R, Fernandez C (2014) Irinotecan and temozolomide brain distribution: a focus on ABCB1. Cancer Chemother Pharmacol 74:185–193. doi:10.1007/s00280-014-2490-0

    Article  CAS  PubMed  Google Scholar 

  23. Achuthan S, Santhoshkumar TR, Prabhakar J, Nair SA, Pillai MR (2011) Drug-induced senescence generates chemoresistant stemlike cells with low reactive oxygen species. J Biol Chem 286:37813–37829. doi:10.1074/jbc.M110.200675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kaufman LJ, Brangwynne CP, Kasza KE, Filippidi E, Gordon VD, Deisboeck TS, Weitz DA (2005) Glioma expansion in collagen I matrices: analyzing collagen concentration-dependent growth and motility patterns. Biophys J 89:635–650. doi:10.1529/biophysj.105.061994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Paulus W, Huettner C, Tonn JC (1994) Collagens, integrins and the mesenchymal drift in glioblastomas: a comparison of biopsy specimens, spheroid and early monolayer cultures. Int J Cancer 58:841–846

    Article  CAS  PubMed  Google Scholar 

  26. Coyle B, Kessler M, Sabnis DH, Kerr ID (2015) ABCB1 in children’s brain tumours. Biochem Soc Trans 43:1018–1022. doi:10.1042/BST20150137

    Article  CAS  PubMed  Google Scholar 

  27. Othman RT, Kimishi I, Bradshaw TD, Storer LC, Korshunov A, Pfister SM, Grundy RG, Kerr ID, Coyle B (2014) Overcoming multiple drug resistance mechanisms in medulloblastoma. Acta Neuropathol Commun 2:57. doi:10.1186/2051-5960-2-57

    Article  PubMed  PubMed Central  Google Scholar 

  28. Colone M, Calcabrini A, Toccacieli L, Bozzuto G, Stringaro A, Gentile M, Cianfriglia M, Ciervo A, Caraglia M, Budillon A, Meo G, Arancia G, Molinari A (2008) The multidrug transporter P-glycoprotein: a mediator of melanoma invasion? J Invest Dermatol 128:957–971. doi:10.1038/sj.jid.5701082

    Article  CAS  PubMed  Google Scholar 

  29. Miletti-Gonzalez KE, Chen S, Muthukumaran N, Saglimbeni GN, Wu X, Yang J, Apolito K, Shih WJ, Hait WN, Rodriguez-Rodriguez L (2005) The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res 65:6660–6667. doi:10.1158/0008-5472.CAN-04-3478

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We deeply appreciate support from the Royal Thai government for a PhD scholarship for WP, and King Abdulaziz University for a PhD scholarship for ABA. This work was supported by funding from the Brain Tumour Charity (SDBTT 17/3). The authors are grateful to Dr Peter Jones (Life Sciences, University of Nottingham) for the generous donation of transwell migration plates.

Author information

Author notes

    Authors and Affiliations

    1. School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

      A. B. Al-Ghafari & I. D. Kerr

    2. School of Medicine, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

      W. Punjaruk, L. C. D. Storer, D. J. Carrier, D. Hussein & B. Coyle

    Authors
    1. A. B. Al-Ghafari
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. W. Punjaruk
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. L. C. D. Storer
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. D. J. Carrier
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. D. Hussein
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. B. Coyle
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. I. D. Kerr
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to B. Coyle or I. D. Kerr.

    Additional information

    A. B. Al-Ghafari and W. Punjaruk have been contributed equally to data generation.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 14 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Al-Ghafari, A.B., Punjaruk, W., Storer, L.C.D. et al. Long-term exposure to irinotecan reduces cell migration in glioma cells. J Neurooncol 127, 455–462 (2016). https://doi.org/10.1007/s11060-016-2058-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11060-016-2058-4

    Keywords

    Search

    Navigation