Journal of Cancer Research and Clinical Oncology

, Volume 140, Issue 8, pp 1343–1352 | Cite as

Re-evaluation of cytostatic therapies for meningiomas in vitro

  • Annette Wilisch-Neumann
  • Doreen Pachow
  • Maren Wallesch
  • Astrid Petermann
  • Frank D. Böhmer
  • Elmar Kirches
  • Christian MawrinEmail author
Original Article – Cancer Research



The purpose was to re-evaluate in cell culture models the therapeutic usefulness of some discussed chemotherapies or targeted therapies for meningiomas with a special emphasis on the role of the neurofibromatosis type 2 (NF2) tumor suppressor, which had been neglected so far. In addition, the study intended to evaluate a potential benefit from a treatment with drugs which are well established in other fields of medicine and have been linked recently with tumor disease by epidemiological studies.


Meningioma cell lines corresponding to various subtypes and pairs of syngenic meningioma cell lines with or without shRNA-induced NF2 knockdown were analyzed for their dose-dependent response to the drugs in microtiter tetrazolium assays, BrdU assays and for selected cases in ELISAs measuring nucleosome liberation to specifically separate cell death from pure inhibition of cell proliferation.


We confirmed a moderate efficacy of hydroxyurea (HU) in clinically relevant concentrations. Under appropriate dosing, we neither detected major responses to the alkylating compound temozolomide nor to various drugs targeting membrane receptors or enzymes (tamoxifen, erlotinib, mifepristone, losartan, metformin and verapamil). Only concentrations far beyond achievable serum levels generated significant effects with the exception of losartan, which showed no effects at all. Chemosensitivity varied markedly among meningioma cell lines. Importantly, cells with NF2 loss exhibited a significantly higher induction of cell death by HU.


Alternative chemotherapeutic or targeted approaches besides HU have still to be evaluated in further studies, and the role of NF2 must be taken into account.


Meningioma Chemotherapy NF2 Radiosensitization 



We thank Emmanuel Antwi-Adjei and Maulana Ikhsan Zain for their help with the experiments. The meningioma research of the group is supported by the Wilhelm-Sander-Stiftung (2010.017.2) and the Deutsche Kinderkrebsstiftung (DKS 2013.04). We are grateful to Helen Morrison for providing reagents.

Conflict of interest



  1. Adams GG, Agrawal S, Sekhri R, Peters MJ, Pierce CM (2013) Appearance and location of retinal haemorrhages in critically ill children. Br J Ophthalmol 97:1138–1142PubMedCrossRefGoogle Scholar
  2. Andersson U, Malmer B, Bergenheim AT, Brannstrom T, Henriksson R (2004) Heterogeneity in the expression of markers for drug resistance in brain tumors. Clin Neuropathol 23:21–27PubMedGoogle Scholar
  3. Andrae N, Kirches E, Hartig R, Haase D, Keilhoff G, Kalinski T, Mawrin C (2012) Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells. Eur J Cancer 48:1831–1841Google Scholar
  4. Bachir D, Hulin A, Huet E, Habibi A, Nzouakou R, El Mahrab M, Astier A, Galacteros F (2007) Plasma and urine hydroxyurea levels might be useful in the management of adult sickle cell disease. Hemoglobin 31:417–425PubMedCrossRefGoogle Scholar
  5. Chamberlain MC (2012) Hydroxyurea for recurrent surgery and radiation refractory high-grade meningioma. J Neurooncol 107:315–321PubMedCrossRefGoogle Scholar
  6. Chamberlain MC, Blumenthal DT (2004) Intracranial meningiomas: diagnosis and treatment. Expert Rev Neurother 4:641–648PubMedCrossRefGoogle Scholar
  7. Chen X, Meng Q, Zhao Y, Liu M, Li D, Yang Y, Sun L, Sui G, Cai L, Dong X (2013) Angiotensin II type 1 receptor antagonists inhibit cell proliferation and angiogenesis in breast cancer. Cancer Lett 328:318–324PubMedCrossRefGoogle Scholar
  8. Cuevas I, Slocum A, Jun P, Costello J, Bollen A, Riggins G, McDermott M, Lal A (2005) Meningioma transcript profiles reveal deregulated Notch signaling pathway. Cancer Res 65:5070–5075PubMedCrossRefGoogle Scholar
  9. Curto M, Cole BK, Lallemand D, Liu CH, McClatchey AI (2007) Contact-dependent inhibition of EGFR signaling by Nf2/merlin. J Cell Biol 177:893–903PubMedCentralPubMedCrossRefGoogle Scholar
  10. de Montalembert M, Bachir D, Hulin A, Gimeno L, Mogenet A, Bresson JL, Macquin-Mavier I, Roudot-Thoraval F, Astier A, Galacteros F (2006) Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease. Haematologica 91:1685–1688PubMedGoogle Scholar
  11. de Robles P, McIntyre J, Kalra S, Roldan G, Cairncross G, Forsyth P, Magliocco T, Hamilton M, Easaw J (2008) Methylation status of MGMT gene promoter in meningiomas. Cancer Genet Cytogenet 187:25–27PubMedCrossRefGoogle Scholar
  12. Demeule M, Shedid D, Beaulieu E, Del Maestro RF, Moghrabi A, Ghosn PB, Moumdjian R, Berthelet F, Beliveau R (2001) Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors. Int J Cancer 93:62–66PubMedCrossRefGoogle Scholar
  13. Eichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, Lynch TJ, Sequist LV (2010) EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neurooncology 12:1193–1199Google Scholar
  14. Fraenzer JT, Pan H, Minimo L Jr, Smith GM, Knauer D, Hung G (2003) Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. Int J Oncol 23:1493–1500PubMedGoogle Scholar
  15. Frishman W, Kirsten E, Klein M, Pine M, Johnson SM, Hillis LD, Packer M, Kates R (1982) Clinical relevance of verapamil plasma levels in stable angina pectoris. Am J Cardiol 50:1180–1184PubMedCrossRefGoogle Scholar
  16. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR et al (2012) Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483:570–575PubMedCentralPubMedCrossRefGoogle Scholar
  17. Goodwin JW, Crowley J, Eyre HJ, Stafford B, Jaeckle KA, Townsend JJ (1993) A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study. J Neurooncol 15:75–77PubMedCrossRefGoogle Scholar
  18. Grunberg S, Weiss M, Russell C, Spitz I, Ahmadi J, Sadun A, Sitruk-Ware R (2006) Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma. Cancer Invest 24:727–733PubMedCrossRefGoogle Scholar
  19. Hahn BM, Schrell UM, Sauer R, Fahlbusch R, Ganslandt O, Grabenbauer GG (2005) Prolonged oral hydroxyurea and concurrent 3d-conformal radiation in patients with progressive or recurrent meningioma: results of a pilot study. J Neurooncol 74:157–165PubMedCrossRefGoogle Scholar
  20. Kajbaf F, Lalau JD (2013) The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis. BMC Pharmacol Toxicol 14:22PubMedCentralPubMedCrossRefGoogle Scholar
  21. Kliese N, Gobrecht P, Pachow D, Andrae N, Wilisch-Neumann A, Kirches E, Riek-Burchardt M, Angenstein F, Reifenberger G, Riemenschneider M, Meese E, Panayotova-Dimitrova D, Gutmann DH, Mawrin C (2013) miRNA-145 is downregulated in atypical and anaplastic meningiomas and negatively regulates motility and proliferation of meningioma cells. Oncogene 32:4712–4720PubMedCrossRefGoogle Scholar
  22. Kyritsis AP (1996) Chemotherapy for meningiomas. J Neurooncol 29:269–272PubMedCrossRefGoogle Scholar
  23. Loubiere C, Dirat B, Tanti JF, Bost F (2013) New perspectives for metformin in cancer therapy. Ann Endocrinol (Paris) 74:130–136CrossRefGoogle Scholar
  24. Loven D, Hardoff R, Sever ZB, Steinmetz AP, Gornish M, Rappaport ZH, Fenig E, Ram Z, Sulkes A (2004) Non-resectable slow-growing meningiomas treated by hydroxyurea. J Neurooncol 67:221–226PubMedCrossRefGoogle Scholar
  25. Madaan K, Kaushik D, Verma T (2012) Hydroxyurea: a key player in cancer chemotherapy. Expert Rev Anticancer Ther 12:19–29PubMedCrossRefGoogle Scholar
  26. Newton HB (2007) Hydroxyurea chemotherapy in the treatment of meningiomas. Neurosurg Focus 23:E11PubMedCrossRefGoogle Scholar
  27. Newton H, Scott S, Volpi C (2004) Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg 18:495–499PubMedCrossRefGoogle Scholar
  28. Norden AD, Drappatz J, Wen PY (2009a) Advances in meningioma therapy. Curr Neurol Neurosci Rep 9:231–240PubMedCrossRefGoogle Scholar
  29. Norden AD, Raizer JJ, Abrey LE, Lamborn KR, Lassman AB, Chang SM, Yung WK, Gilbert MR, Fine HA, Mehta M, Deangelis LM, Cloughesy TF, Robins HI, Aldape K, Dancey J, Prados MD et al (2009b) Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma. J NeurooncolGoogle Scholar
  30. Pachow D, Andrae N, Kliese N, Angenstein F, Stork O, Wilisch-Neumann A, Kirches E, Mawrin C (2013) mTORC1 inhibitors suppress meningioma growth in mouse models. Clin Cancer Res 19:1180–1189PubMedCrossRefGoogle Scholar
  31. Preusser M, Berghoff AS, Hottinger AF (2013) High-grade meningiomas: New avenues for drug treatment? Curr Opin Neurol 26:708–715PubMedCrossRefGoogle Scholar
  32. Puttmann S, Senner V, Braune S, Hillmann B, Exeler R, Rickert CH, Paulus W (2005) Establishment of a benign meningioma cell line by hTERT-mediated immortalization. Lab Invest 85:1163–1171PubMedCrossRefGoogle Scholar
  33. Reardon DA, Norden AD, Desjardins A, Vredenburgh JJ, Herndon JE 2nd, Coan A, Sampson JH, Gururangan S, Peters KB, McLendon RE, Norfleet JA, Lipp ES, Drappatz J, Wen PY, Friedman HS (2012) Phase II study of Gleevec((R)) plus hydroxyurea (HU) in adults with progressive or recurrent meningioma. J Neurooncol 106:409–415PubMedCentralPubMedCrossRefGoogle Scholar
  34. Schrell UM, Rittig MG, Anders M, Koch UH, Marschalek R, Kiesewetter F, Fahlbusch R (1997) Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea. J Neurosurg 86:840–844PubMedCrossRefGoogle Scholar
  35. Striedinger K, Vandenberg SR, Baia GS, McDermott MW, Gutmann DH, Lal A (2008) The neurofibromatosis 2 tumor suppressor gene product, merlin, regulates human meningioma cell growth by signaling through YAP. Neoplasia 10:1204–1212PubMedCentralPubMedGoogle Scholar
  36. Tanaka K, Sato C, Maeda Y, Koike M, Matsutani M, Yamada K, Miyaki M (1989) Establishment of a human malignant meningioma cell line with amplified c-myc oncogene. Cancer 64:2243–2249PubMedCrossRefGoogle Scholar
  37. Teft WA, Gong IY, Dingle B, Potvin K, Younus J, Vandenberg TA, Brackstone M, Perera FE, Choi YH, Zou G, Legan RM, Tirona RG, Kim RB (2013) CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. Breast Cancer Res Treat 139:95–105PubMedCrossRefGoogle Scholar
  38. Tsubata Y, Hamada A, Sutani A, Isobe T (2012) Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient. J Cancer Res Ther 8:154–156PubMedCrossRefGoogle Scholar
  39. Wilisch-Neumann A, Kliese N, Pachow D, Schneider T, Warnke JP, Braunsdorf WE, Bohmer FD, Hass P, Pasemann D, Helbing C, Kirches E, Mawrin C (2013) The integrin inhibitor cilengitide affects meningioma cell motility and invasion. Clin Cancer Res 19:5402–5412PubMedCrossRefGoogle Scholar
  40. Zhou L, Hanemann CO (2012) Merlin, a multi-suppressor from cell membrane to the nucleus. FEBS Lett 586:1403–1408PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Annette Wilisch-Neumann
    • 1
  • Doreen Pachow
    • 1
  • Maren Wallesch
    • 1
  • Astrid Petermann
    • 2
  • Frank D. Böhmer
    • 2
  • Elmar Kirches
    • 1
  • Christian Mawrin
    • 1
    Email author
  1. 1.Department of NeuropathologyOtto-von-Guericke UniversityMagdeburgGermany
  2. 2.Institute of Molecular Cell Biology, CMBJena University HospitalJenaGermany

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