Abstract
Statins are inhibitors of the cholesterol synthesis pathway with pleiotropic effects, while thiazolidinediones (TDZ) are peroxisomal proliferator activator receptor γ (PPAR-γ) agonists with potent proapoptotic activity. For both groups of substances a cytotoxic effect against several human tumors is presumed. Direct comparison of several statins and TDZ has not been performed on meningioma cells until now. We compared the antiproliferative/cytotoxic effect of five statins, two TDZ, and their combinations on various human meningioma cell lines and nontumorous cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, cell cycle analysis, and caspase-3 assay. Simvastatin (SMV) and its combination with the TDZ pioglitazone (PGZ) turned out to be the most effective treatment. After 96 h the 50% inhibition concentration (IC50) of SMV in MTT assays for two more sensitive meningioma cell lines (one benign and one malignant) was below 0.9 μM, while the IC50 was 2.8 μM or higher for two other meningioma lines. Fluorescence-activated cell sorting (FACS) analysis suggested that MTT results mostly represented cytotoxic rather than antiproliferative effects. Strong caspase-3 induction suggested participation of intrinsic apoptosis in meningioma cell death. In contrast, SMV showed no substantial effects on fibroblasts and astrocytes. Addition of 40 μM PGZ significantly decreased the fraction of clonogenic cells in soft-agar assays, as compared with 2.8 μM SMV alone. Taken together, SMV showed a significant cytotoxic effect against human meningioma cells, which was moderately enhanced by PGZ.
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Kalamarides M, Stemmer-Rachamimov AO, Takahashi M, Han ZY, Chareyre F, Niwa-Kawakita M et al (2008) Natural history of meningioma development in mice reveals: a synergy of Nf2 and p16(Ink4a) mutations. Brain Pathol 18(1):62–70
Simpson D (1957) The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 20(1):22–39
Jaaskelainen J (1986) Seemingly complete removal of histologically benign intracranial meningioma: late recurrence rate and factors predicting recurrence in 657 patients. A multivariate analysis. Surg Neurol 26(5):461–469
Durand A, Labrousse F, Jouvet A, Bauchet L, Kalamarides M, Menei P et al (2009) WHO grade II and III meningiomas: a study of prognostic factors. J Neurooncol 95(3):367–375
Schrell UM, Rittig MG, Anders M, Koch UH, Marschalek R, Kiesewetter F et al (1997) Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea. J Neurosurg 86(5):840–844
Newton HB (2007) Hydroxyurea chemotherapy in the treatment of meningiomas. Neurosurg Focus 23(4):E11
Hindler K, Cleeland CS, Rivera E, Collard CD (2006) The role of statins in cancer therapy. Oncologist 11(3):306–315
Jiang Z, Zheng X, Lytle RA, Higashikubo R, Rich KM (2004) Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in glioblastoma cells. J Neurochem 89(1):168–178
Cemeus C, Zhao TT, Barrett GM, Lorimer IA, Dimitroulakos J (2008) Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status. J Neurooncol 90(1):9–17
Johnson MD, Woodard A, Okediji EJ, Toms SA, Allen GS (2002) Lovastatin is a potent inhibitor of meningioma cell proliferation: evidence for inhibition of a mitogen associated protein kinase. J Neurooncol 56(2):133–142
Mawrin C, Sasse T, Kirches E, Kropf S, Schneider T, Grimm C et al (2005) Different activation of mitogen-activated protein kinase and Akt signaling is associated with aggressive phenotype of human meningiomas. Clin Cancer Res 11(11):4074–4082
Chou FS, Wang PS, Kulp S, Pinzone JJ (2007) Effects of thiazolidinediones on differentiation, proliferation, and apoptosis. Mol Cancer Res 5(6):523–530
Spagnolo A, Grant EN, Glick R, Lichtor T, Feinstein DL (2007) Differential effects of PPARgamma agonists on the metabolic properties of gliomas and astrocytes. Neurosci Lett 417(1):72–77
Papi A, Tatenhorst L, Terwel D, Hermes M, Kummer MP, Orlandi M et al (2009) PPARgamma and RXRgamma ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models. J Neurochem 109(6):1779–1790
Yao CJ, Lai GM, Chan CF, Cheng AL, Yang YY, Chuang SE (2006) Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone. Int J Cancer 118(3):773–779
Haase D, Schmidl S, Ewald C, Kalff R, Huebner C, Firsching R et al. Fatty acid synthase as a novel target for meningioma therapy. p. noq004
Mason RP, Walter MF, Day CA, Jacob RF (2005) Intermolecular differences of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors contribute to distinct pharmacologic and pleiotropic actions. Am J Cardiol 96(5A):11F–23F
Sironi L, Gianazza E, Gelosa P, Guerrini U, Nobili E, Gianella A et al (2005) Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects. Arterioscler Thromb Vasc Biol 25(3):598–603
Grommes C, Landreth GE, Sastre M, Beck M, Feinstein DL, Jacobs AH et al (2006) Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor gamma agonist treatment. Mol Pharmacol 70(5):1524–1533
Spagnolo A, Glick RP, Lin H, Cohen EP, Feinstein DL, Lichtor T (2007) Prolonged survival of mice with established intracerebral glioma receiving combined treatment with peroxisome proliferator-activated receptor-gamma thiazolidinedione agonists and interleukin-2-secreting syngeneic/allogeneic fibroblasts. J Neurosurg 106(2):299–305
Xue YJ, Turner KC, Meeker JB, Pursley J, Arnold M, Unger S (2003) Quantitative determination of pioglitazone in human serum by direct-injection high-performance liquid chromatography mass spectrometry and its application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci 795(2):215–226
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(11):1204–1212
Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S et al (2003) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci 23(35):11104–11111
Johnson M, Toms S (2005) Mitogenic signal transduction pathways in meningiomas: novel targets for meningioma chemotherapy? J Neuropathol Exp Neurol 64(12):1029–1036
Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl RJ et al (1996) Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 2(3):483–491
Gabrys D, Doerfler A, Yaromina A, Hessel F, Krause M, Oertel R, Baumann M (2008) Effects of lovastatine alone or combined with irradiation on tumor cells in vitro and in vivo. Strahlenther Onkol 184:48–53
Maeshiba Y, Kiyota Y, Yamashita K, Yoshimura Y, Motohashi M, Tanayama S (1997) Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys. Arzneimittelforschung 47(1):29–35
Bitzer M, Nagele T, Geist-Barth B, Klose U, Gronewaller E, Morgalla M et al (2000) Role of hydrodynamic processes in the pathogenesis of peritumoral brain edema in meningiomas. J Neurosurg 93(4):594–604
Vignes JR, Sesay M, Rezajooi K, Gimbert E, Liguoro D (2008) Peritumoral edema and prognosis in intracranial meningioma surgery. J Clin Neurosci 15(7):764–768
Cafforio P, Dammacco F, Gernone A, Silvestris F (2005) Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 26(5):883–891
Dimitroulakos J, Marhin WH, Tokunaga J, Irish J, Gullane P, Penn LZ et al (2002) Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. Neoplasia 4(4):337–346
Agarwal B, Bhendwal S, Halmos B, Moss SF, Ramey WG, Holt PR (1999) Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin Cancer Res 5(8):2223–2229
Dimitroulakos J, Thai S, Wasfy GH, Hedley DW, Minden MD, Penn LZ (2000) Lovastatin induces a pronounced differentiation response in acute myeloid leukemias. Leuk Lymphoma 40(1–2):167–178
Chan DY, Chen GG, Poon WS, Liu PC (2008) Lovastatin sensitized human glioblastoma cells to TRAIL-induced apoptosis. J Neurooncol 86(3):273–283
Tanaka T, Tatsuno I, Uchida D, Moroo I, Morio H, Nakamura S et al (2000) Geranylgeranyl-pyrophosphate, an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by 3-hydroxy-3-methylglutaryl-CoA reductase inhibition. J Neurosci 20(8):2852–2859
Perez-Ortiz JM, Tranque P, Vaquero CF, Domingo B, Molina F, Calvo S et al (2004) Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma. J Biol Chem 279(10):8976–8985
Kondo M, Oya-Ito T, Kumagai T, Osawa T, Uchida K (2001) Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress. J Biol Chem 276(15):12076–12083
Baia GS, Dinca EB, Ozawa T, Kimura ET, McDermott MW, James CD et al (2008) An orthotopic skull base model of malignant meningioma. Brain Pathol 18(2):172–179
Acknowledgment
This work was supported in part by a grant from the Deutsche Krebshilfe to C.M. and E.K. (grant number 108987).
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Authors Thomas Schneider and Christian Mawrin contributed equally.
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Gehring, S., Tapia-Pérez, J.H., Kirches, E. et al. Cytotoxic effects of statins and thiazolidinediones on meningioma cells. J Neurooncol 102, 383–393 (2011). https://doi.org/10.1007/s11060-010-0351-1
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DOI: https://doi.org/10.1007/s11060-010-0351-1