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Re-evaluation of cytostatic therapies for meningiomas in vitro

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  • Adams GG, Agrawal S, Sekhri R, Peters MJ, Pierce CM (2013) Appearance and location of retinal haemorrhages in critically ill children. Br J Ophthalmol 97:1138–1142

    Article  CAS  PubMed  Google Scholar 

  • 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 23:21–27

    CAS  PubMed  Google Scholar 

  • 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 48:1831–1841

  • 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 31:417–425

    Article  CAS  PubMed  Google Scholar 

  • Chamberlain MC (2012) Hydroxyurea for recurrent surgery and radiation refractory high-grade meningioma. J Neurooncol 107:315–321

    Article  CAS  PubMed  Google Scholar 

  • Chamberlain MC, Blumenthal DT (2004) Intracranial meningiomas: diagnosis and treatment. Expert Rev Neurother 4:641–648

    Article  PubMed  Google Scholar 

  • 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 328:318–324

    Article  CAS  PubMed  Google Scholar 

  • 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 65:5070–5075

    Article  CAS  PubMed  Google Scholar 

  • Curto M, Cole BK, Lallemand D, Liu CH, McClatchey AI (2007) Contact-dependent inhibition of EGFR signaling by Nf2/merlin. J Cell Biol 177:893–903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 91:1685–1688

    PubMed  Google Scholar 

  • 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 187:25–27

    Article  PubMed  Google Scholar 

  • 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 93:62–66

    Article  CAS  PubMed  Google Scholar 

  • 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 12:1193–1199

    CAS  Google Scholar 

  • 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 23:1493–1500

    CAS  PubMed  Google Scholar 

  • 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 50:1180–1184

    Article  CAS  PubMed  Google Scholar 

  • 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 483:570–575

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 15:75–77

    Article  CAS  PubMed  Google Scholar 

  • 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 24:727–733

    Article  CAS  PubMed  Google Scholar 

  • 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 74:157–165

    Article  CAS  PubMed  Google Scholar 

  • 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 14:22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 32:4712–4720

    Article  CAS  PubMed  Google Scholar 

  • Kyritsis AP (1996) Chemotherapy for meningiomas. J Neurooncol 29:269–272

    Article  CAS  PubMed  Google Scholar 

  • Loubiere C, Dirat B, Tanti JF, Bost F (2013) New perspectives for metformin in cancer therapy. Ann Endocrinol (Paris) 74:130–136

    Article  CAS  Google Scholar 

  • 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 67:221–226

    Article  PubMed  Google Scholar 

  • Madaan K, Kaushik D, Verma T (2012) Hydroxyurea: a key player in cancer chemotherapy. Expert Rev Anticancer Ther 12:19–29

    Article  CAS  PubMed  Google Scholar 

  • Newton HB (2007) Hydroxyurea chemotherapy in the treatment of meningiomas. Neurosurg Focus 23:E11

    Article  PubMed  Google Scholar 

  • Newton H, Scott S, Volpi C (2004) Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg 18:495–499

    Article  CAS  PubMed  Google Scholar 

  • Norden AD, Drappatz J, Wen PY (2009a) Advances in meningioma therapy. Curr Neurol Neurosci Rep 9:231–240

    Article  CAS  PubMed  Google Scholar 

  • 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 Neurooncol

  • 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 19:1180–1189

    Article  CAS  PubMed  Google Scholar 

  • Preusser M, Berghoff AS, Hottinger AF (2013) High-grade meningiomas: New avenues for drug treatment? Curr Opin Neurol 26:708–715

    Article  CAS  PubMed  Google Scholar 

  • 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 85:1163–1171

    Article  PubMed  Google Scholar 

  • 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 106:409–415

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 86:840–844

    Article  CAS  PubMed  Google Scholar 

  • 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 10:1204–1212

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 64:2243–2249

    Article  CAS  PubMed  Google Scholar 

  • 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 139:95–105

    Article  CAS  PubMed  Google Scholar 

  • 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 8:154–156

    Article  PubMed  Google Scholar 

  • 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 19:5402–5412

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Hanemann CO (2012) Merlin, a multi-suppressor from cell membrane to the nucleus. FEBS Lett 586:1403–1408

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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

None.

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Authors and Affiliations

  1. Department of Neuropathology, Otto-von-Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany

    Annette Wilisch-Neumann, Doreen Pachow, Maren Wallesch, Elmar Kirches & Christian Mawrin

  2. Institute of Molecular Cell Biology, CMB, Jena University Hospital, Jena, Germany

    Astrid Petermann & Frank D. Böhmer

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  1. Annette Wilisch-Neumann
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  2. Doreen Pachow
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  3. Maren Wallesch
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  6. Elmar Kirches
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  7. Christian Mawrin
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Correspondence to Christian Mawrin.

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Wilisch-Neumann, A., Pachow, D., Wallesch, M. et al. Re-evaluation of cytostatic therapies for meningiomas in vitro. J Cancer Res Clin Oncol 140, 1343–1352 (2014). https://doi.org/10.1007/s00432-014-1683-6

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  • DOI: https://doi.org/10.1007/s00432-014-1683-6

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