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Tumor-inhibition effect of levetiracetam in combination with temozolomide in glioblastoma cells

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Abstract

Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis. The standard postoperative chemotherapy is temozolomide (TMZ), which does not greatly improve survival. The DNA repair gene O-6-methylguanine-DNA methyltransferase (MGMT) contributes to the response of TMZ-induced DNA damage. The commonly prescribed antiepileptic drug levetiracetam (LEV) has been shown to enhance TMZ’s antitumor effect via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of the LEV and TMZ combination remain poorly understood. Mechanisms of response to chemotherapy include apoptosis and mitotic catastrophe, and recent studies have suggested that premature senescence may also be invoked when cancer cells are exposed to therapeutic agents. In our study, we evaluated cell proliferation and premature senescence after single and combined treatments of TMZ and LEV in two GBM cell lines that differ in TMZ sensitivity caused by the absence (A172) or presence (T98) of the MGMT protein. Both LEV and TMZ reduced cell proliferation in a dose-dependent manner in A172 cells. A senescent-like phenotype, as determined by β-galactosidase activity, was induced by both TMZ and LEV. Overall, there was a greater effect following combined treatment compared to the monotherapy groups. Thus, LEV appears to have a tumor-suppressive effect and induces cellular senescence, and combined treatment of LEV and TMZ enhanced these effects. because LEV treatment results in few adverse effects, its use in GBM treatment may allow for reduction of the TMZ dose to enhance the clinical efficacy of TMZ chemotherapy and improve quality of life.

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References

  1. Stupp, R., Hegi, M.E., Mason, W.P., van den Bent, M.J., Taphoorn, M.J., Janzer, R.C., Ludwin, S.K., Allgeier, A., Fisher, B., Belanger, K., Hau, P., Brandes, A.A., Gijtenbeek, J., Marosi, C., Vecht, C.J., Mokhtari, K., Wesseling, P., Villa, S., Eisenhauer, E., Gorlia, T., Weller, M., Lacombe, D., Cairncross, J.G., and Mirimanoff, R.O., Lancet Oncol., 2009, vol. 10, pp. 459–466.

    Article  CAS  PubMed  Google Scholar 

  2. Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Brandes, A.A., Marosi, C., Bogdahn, U., Curschmann, J., Janzer, R.C., Ludwin, S.K., Gorlia, T., Allgeier, A., Lacombe, D., Cairncross, J.G., Eisenhauer, E., and Mirimanoff, R.O.., N. Engl. J. Med., 2005, vol. 352, pp. 987–996.

    Article  CAS  PubMed  Google Scholar 

  3. Milligan, T.A., Hurwitz, S., and Bromfield, E.B., Neurology, 2008, vol. 71, pp. 665–669.

    Article  CAS  PubMed  Google Scholar 

  4. Motomura, K., Natsume, A., Kishida, Y., Higashi, H., Kondo, Y., Nakasu, Y., Abe, T., Namba, H., Wakai, K., and Wakabayashi, T., Cancer, 2011, vol. 117, pp. 1721–1730.

    Article  CAS  PubMed  Google Scholar 

  5. Kim, Y.H., Kim, T., Joo, J.D., Han, J.H., Kim, Y.J., Kim, I.A., Yun, C.H., and Kim, C.Y., Cancer, 2015, vol. 121, pp. 2926–2932.

    Article  CAS  PubMed  Google Scholar 

  6. Lin, C.J., Lee, C.C., Shih, Y.L., Lin, T.Y., Wang, S.H., Lin, Y.F., and Shih, C.M., Free Radic. Biol. Med., 2012, vol. 52, pp. 377–391.

    Article  CAS  PubMed  Google Scholar 

  7. Yamada, S., Matsuda, R., Nishimura, F., Nakagawa I., Motoyama, Y., Park, Y.S., Nakamura, M., Nakase, H., Ouji, Y., and Yoshikawa, M., Exp. Ther. Med., 2012, vol. 4, pp. 21–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Rossetti, A.O. and Stupp, R., Curr. Opin. Neurol., 2010, vol. 23, pp. 603–609.

    Article  CAS  PubMed  Google Scholar 

  9. Kargiotis, O., Markoula, S., and Kyritsis, A.P., Cancer Chemother. Pharmacol., 2011, vol. 67, pp. 489–501.

    Article  CAS  PubMed  Google Scholar 

  10. Jaeckle, K.A., Ballman, K., Furth, A., and Buckner, J.C., Neurology, 2009, vol. 73, pp. 1207–1213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Perucca, E. and Tomson, T., Lancet Neurol., 2011, vol. 10, pp. 446–456.

    Article  CAS  PubMed  Google Scholar 

  12. Rosati, A., Buttolo, L., Stefini, R., Todeschini, A., Cenzato, M., and Padovani, A., Arch. Neurol., 2010, vol. 67, pp. 343–346.

    Article  PubMed  Google Scholar 

  13. Fonkem, E., Bricker, P., Mungall, D., Aceves, J., Ebwe, E., Tang, W., and Kirmani, B., Front. Neurol., 2013, vol. 4, p.153.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee, Y.J., Kim, T., Bae, S.H., Kim, Y.H., Han, J.H., Yun, C.H., and Kim, C.Y., CNS Drugs, 2013, vol. 27, pp. 753–759.

    Article  CAS  PubMed  Google Scholar 

  15. Gewirtz, D.A., Autophagy, 2009, vol. 5, pp. 1232–1234.

    Article  PubMed  Google Scholar 

  16. Bobustuc, G.C., Baker, C.H., Limaye, A., Jenkins, W.D., Pearl, G., Avgeropoulos, N.G., and Konduri, S.D., Neuro-oncology, 2010, vol. 12, pp. 917–927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Courtois-Cox, S., Jones, S.L., and Cichowski, K., Oncogene, 2008, vol. 27, 2801–2809.

    Article  CAS  PubMed  Google Scholar 

  18. Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., and Lowe, S.W., Nature, 2007, vol. 445, pp. 656–660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Campisi, J. and d’Adda di Fagagna, F., Nat. Rev. Mol. Cell Biol., 2007, vol. 8, pp. 729–740.

    Article  CAS  PubMed  Google Scholar 

  20. Kern, K., Schebesch, K.M., Schlaier, J., Hansen, E., Feigl, G.C., Brawanski, A.T., and Lange, M.., J. Clin. Neurosci., 2012, vol. 19, pp. 99–100.

    Article  CAS  PubMed  Google Scholar 

  21. Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A.J., Barradas, M., Benguría, A., Zaballos, A., Flores, J.M., Barbacid, M., Beach, D., and Serrano, M., Nature, 2005, vol. 436, p.642.

    Article  CAS  PubMed  Google Scholar 

  22. Ryu, C.H., Yoon, W.S., Park, K.Y., Kim, S.M., Lim, J.Y., Woo, J.S., Jeong, C.H., Hou, Y., and Jeun, S.S.., J. Biomed. Biotechnol. 2012, vol. 2012, p. 987495.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Garcia-Manero, G., Yang, H., Bueso-Ramos, C., Ferrajoli, A., Cortes, J., Wierda, W.G., Faderl, S., Koller, C., Morris, G., Rosner, G., Loboda, A., Fantin, V.R., Randolph, S.S., Hardwick, J.S., Reilly, J.F., Chen, C., Ricker, J.L., Secrist, J.P., Richon, V.M., Frankel, S.R., and Kantarjian, H.M., Blood, 2008, vol. 111, pp. 1060–1066.

    Article  CAS  PubMed  Google Scholar 

  24. Osuka, S., Takano, S., Watanabe, S., Ishikawa, E., Yamamoto, T., and Matsumura, A., Neurol. Med. Chir. (Tokyo), 2012, vol. 52, pp. 186–193.

    Article  Google Scholar 

  25. Ryu, C.H., Park, K.Y., Kim, S.M., Jeong, C.H., Woo, J.S., Hou, Y., and Jeun, S.S., Biochem. Biophys. Res. Commun., 2012, vol. 421, pp. 585–590.

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, Y., Xu, Y., Wang, H., Niu, J., Hou, H., and Jiang, Y., Oncol. Lett. 2014, vol. 7, pp. 203–208.

    CAS  PubMed  Google Scholar 

  27. Li, X.N., Shu, Q., Su, J.M., Perlaky, L., Blaney, S.M., and Lau, C.C., Mol. Cancer Ther., 2005, vol. 4, no. 12, pp. 1912–1922.

    Article  CAS  PubMed  Google Scholar 

  28. Eyal, S., Yagen, B., Sobol, E., Altschuler, Y., Shmuel, M., and Bialer, M., Epilepsia, 2004, vol. 45, no. 7, pp. 737–744.

    Article  CAS  PubMed  Google Scholar 

  29. de Groot, M., Douw, L., Sizoo, E.M., Bosma, I., Froklage, F.E., Heimans, J.J., Postma, T.J., Klein, M., and Reijneveld, J.C., Neuro-oncology, 2013, vol. 15, pp. 216–223.

    Article  PubMed  Google Scholar 

  30. Cardile, V., Pavone, A., Gulino, R., Renis, M., Scifo, C., and Perciavalle, V., Brain Res., 2003, vol. 976, no. 2, pp. 227–233.

    Article  CAS  PubMed  Google Scholar 

  31. Ueda, Y., Doi, T., Takaki, M., Nagatomo, K., Nakajima, A., and Willmore, L.J., Brain Res., 2009, vol. 1266, pp. 1–7.

    Article  CAS  PubMed  Google Scholar 

  32. Custer, K.L., Austin, N.S., Sullivan, J.M., and Bajjalieh, S.M., J. Neurosci., 2006, vol. 26, pp. 1303–1313.

    Article  CAS  PubMed  Google Scholar 

  33. de Groot, M., Aronica, E., Heimans, J.J., and Reijneveld, J.C., Neurology, 2011, vol. 77, pp. 532–539.

    Article  PubMed  Google Scholar 

  34. Nakada, M., Furuta, T., Hayashi, Y., Minamoto, T., and Hamada, J., Front. Oncol., 2012, vol. 2, p.98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shay, J.W. and Roninson, I.B., Oncogene, 2004, vol. 23, pp. 2919–2933.

    Article  CAS  PubMed  Google Scholar 

  36. Litwiniec, A., Grzanka, A., Helmin-Basa, A., Gackowska, L., and Grzanka, D., J. Cancer Res. Clin. Oncol., 2010, vol. 136, pp. 717–736.

    Article  CAS  PubMed  Google Scholar 

  37. Rebbaa, A., Cancer Lett., 2005, vol. 219, pp. 1–13.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Nara Medical University of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan

    A. Marutani, M. Nakamura, F. Nishimura, T. Nakazawa, R. Matsuda, Y. Hironaka, I. Nakagawa, K. Tamura, Y. Takeshima, Y. Motoyama, E. Boku & H. Nakase

  2. Department of Pathogen, Infection and Immunity, Nara Medical University of Medicine, Nara, Japan

    Y. Ouji & M. Yoshikawa

Authors
  1. A. Marutani
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  2. M. Nakamura
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  3. F. Nishimura
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  4. T. Nakazawa
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Correspondence to M. Nakamura.

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Marutani, A., Nakamura, M., Nishimura, F. et al. Tumor-inhibition effect of levetiracetam in combination with temozolomide in glioblastoma cells. Neurochem. J. 11, 43–49 (2017). https://doi.org/10.1134/S1819712416040073

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  • DOI: https://doi.org/10.1134/S1819712416040073

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