Investigational New Drugs

, Volume 36, Issue 1, pp 28–35 | Cite as

The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells

  • Ludovica Taglieri
  • Giovanna Rubinacci
  • Anna Giuffrida
  • Simone Carradori
  • Susanna ScarpaEmail author


Glioblastoma multiforme is the most common primary malignant brain tumor and its current chemotherapeutic options are limited to temozolomide. Recently, some synthetic compounds acting as inhibitors of kinesin spindle protein Eg5 have shown pronounced antitumor activity. Our group has recently demonstrated that one of these kinesin Eg5 inhibitors, named K858, exerted important antiproliferative and apoptotic effects on breast cancer cells. Since glioblastoma cells usually express high levels of kinesin Eg5, we tested the effect of K858 on two human glioblastoma cell lines (U-251 and U-87) and found that K858 inhibited cell growth, induced apoptosis, reversed epithelial-mesenchymal transition and inhibited migration in both cell lines. We also detected that, at the same time, K858 increased the expression of survivin, an anti-apoptotic molecule, and that the forced down-regulation of survivin, obtained with the specific inhibitor YM155, boosted K858-dependent apoptosis. This indicated that the anti-tumor activity of K858 on glioblastoma cells is limited by the over-expression of survivin and that the negative regulation of this protein sensitizes tumor cells to K858. These data confirmed that kinesin Eg5 is an interesting target for new therapeutic approaches for glioblastoma. We showed that K858, specifically, was a potent inhibitor of replication, an inducer of apoptosis and a negative regulator of the invasive phenotype for glioblastoma cells.


Glioblastoma Kinesin Eg5 K858 Apoptosis Tumor invasion Survivin 



This research was supported by no specific grant.

Compliance with ethical standards

Conflict of interest

All individual authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in this study.


  1. 1.
    Muller C, Gross D, Sarli V, Gartner M, Giannis A, Bernhardt G, Buschauer A (2007) Inhibitors of kinesin Eg5: antiproliferative activity of monastrol analogues against human glioblastoma cells. Cancer Chemother Pharmacol 59:157–164CrossRefPubMedGoogle Scholar
  2. 2.
    Liu L, Liu X, Mare M, Dumont AS, Zhang H, Yan D, Xiong Z (2016) Overexpression of Eg5 correlates with high grade astrocytic neoplasm. J Neuro-Oncol 126:77–80CrossRefGoogle Scholar
  3. 3.
    Valensin S, Ghiron C, Lamanna C, Kremer A, Rossi M, Ferruzzi P, Nievo M, Bakker A (2009) KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain? BMC Cancer 9:196CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Venere M, Horbinski C, Crish JF, Jin X, Vasanji A, Major J, Burrows AC, Chang C, Prokop J, Wu Q, Sims PA, Canoll P, Summers MK, Rosenfeld SS, Rich JN (2015) The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma. Sci Transl Med 7:304ra143Google Scholar
  5. 5.
    Rath O, Kozielski F (2012) Kinesins and cancer. Nat Rev Cancer 12:527–539CrossRefPubMedGoogle Scholar
  6. 6.
    Cioroiu C, Weimer LH (2017) Update on chemotherapy-induced peripheral neuropathy. Curr Neurol Neurosci Rep 17:47CrossRefPubMedGoogle Scholar
  7. 7.
    Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–974CrossRefPubMedGoogle Scholar
  8. 8.
    Sarli V, Huemmer S, Sunder-Plassmann N, Mayer TU, Giannis A (2005) Synthesis and biological evaluation of novel Eg5 inhibitors. Chembiochem 6:2005–2013CrossRefPubMedGoogle Scholar
  9. 9.
    Nakai R, Iida S, Takahashi T, Tsujita T, Okamoto S, Takada C, Akasaka K, Ichikawa S, Ishida H, Kusaka H, Akinaga S, Murakata C, Honda S, Nitta M, Saya H, Yamashita Y (2009) K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res 69:3901–3909CrossRefPubMedGoogle Scholar
  10. 10.
    De Iuliis F, Taglieri L, Salerno G, Giuffrida A, Milana B, Giantulli S, Carradori S, Silvestri I, Scarpa S (2016) The kinesin Eg5 inhibitor K858 induces apoptosis but also surviving-related chemoresistance in breast cancer cells. Investig New Drugs 34:399–406CrossRefGoogle Scholar
  11. 11.
    Tastekin E, Caloglu VY, Puyan FO, Tokuc B, Caloglu M, Yalta TD, Can N, Guler B (2016) Prognostic value of angiogenesis and survivin expression in patients with glioblastoma. Turk Neurosurg 26:484–490PubMedGoogle Scholar
  12. 12.
    Clark MJ, Homer N, O’Connor BD, Chen Z, Eskin A, Lee H, Merriman B, Nelson SF (2010) U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line. PLoS Genet 6:e1000832CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bigner DD, Bigner SH, Ponten J, Westermark B, Mahaley MS, Ruoslahti E, Herschman H, Eng LF, Wikstrand CJ (1981) Heterogeneity of genotypic and phenotypic characteristics of fifteen permanent cell lines derived from human gliomas. J Neuropathol Exp Neurol 40:201–229CrossRefPubMedGoogle Scholar
  14. 14.
    Tang D, Lahti JM, Kidd VJ (2000) Caspase-8 activation and bid cleavage contribute to MCF7 cellular execution in a caspase-3 dependent manner during staurosporine-mediated apoptosis. J Biol Chem 275:9303–9307CrossRefPubMedGoogle Scholar
  15. 15.
    Asraf H, Avunie-Masala R, Hershfinkel M, Gheber L (2015) Mitotic slippage and expression of survivin are linked to differential sensitivity of human cancer cell-lines to the kinesin-5 inhibitor monastrol. PLoS One 10:e0129255CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kast RE, Skuli N, Karpel-Massler G, Frosina G, Ryken T, Halatsch ME (2017) Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen. Oncotarget.
  17. 17.
    Rello-Varona S, Vitale I, Kepp O, Senovilla L, Jemaà M, Metivier D, Castedo M, Kroemer G (2009) Preferential killing of tetraploid tumor cells by targeting the mitotic kinesin Eg5. Cell Cycle 8:1030–1035CrossRefPubMedGoogle Scholar
  18. 18.
    Koller E, Propp S, Zhang H, Zhao C, Xiao X, Chang M, Hirsch SA, Shepard PJ, Koo S, Murphy C, Glazer RI, Dean NM (2006) Use of a chemically modified antisense oligonucleotide library to identify and validate Eg5 (kinesin-like 1) as a target for antineoplastic drug development. Cancer Res 66:2059–2066CrossRefPubMedGoogle Scholar
  19. 19.
    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, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  20. 20.
    De Iuliis F, Salerno G, Giuffrida A, Milana B, Taglieri L, Rubinacci G, Giantulli S, Terella F, Silvestri I, Scarpa S (2016) Breast cancer cells respond differently to docetaxel depending on their phenotype and on survivin upregulation. Tumor Biol 37:2603–2611CrossRefGoogle Scholar
  21. 21.
    Lens SM, Wolthuis RM, Klompmaker R, Kauw J, Agami R, Brummelkamp T, Kops G, Medema RH (2003) Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J 22:2934–2347CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Georgakilas AG, Martin OA, Bonner WM (2017) p21: A two-faced genome guardian. Trends Mol Med 23:310–319CrossRefPubMedGoogle Scholar
  23. 23.
    Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9:400–414CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yoon MK, Mitrea DM, Ou L, Kriwacki RW (2012) Cell cycle regulation by the intrinsically disordered proteins p21 and p27. Biochem Soc Trans 40:981–988CrossRefPubMedGoogle Scholar
  25. 25.
    Zhu T, Li X, Luo L, Wang X, Li Z, Xie P, Gao X, Song Z, Su J, Liang G (2015) Reversion of malignant phenotypes of human glioblastoma cells by beta-elemene through beta-catenin-mediated regulation of stemness-, differentiation- and epithelial-to-mesenchymal transition-related molecules. J Transl Med 13:356–370CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    He X, Liu Z, Peng Y, Yu C (2016) Micro RNA-181c inhibits glioblastoma cell invasion, migration and mesenchymal transition by targeting TGF-beta pathway. Bioch Biophys Res Commun 469:1041–1048CrossRefGoogle Scholar
  27. 27.
    Yang WH, Su YH, Hsu WH, Wang CC, Arbiser JL, Yang MH (2016) Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation. Oncogene 35:2287–2289CrossRefPubMedGoogle Scholar
  28. 28.
    Falnikar A, Tole S, Baas PW (2011) Kinesin-5, a mitotic microtubule-associated motor protein, modulates neuronal migration. Mol Biol Cell 22:1561–1574CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wang F, Lin SL (2014) Knockdown of kinesin KIF11 abrogates directed migration in response to epidermal growth factor-mediated chemotaxis. Bioch Biophys Res Commun 452:642–648CrossRefGoogle Scholar
  30. 30.
    Sun XD, Shi XJ, Sun XO, Luo YG, Wu XJ, Yao CF, Yu HY, Li DW, Liu M, Zhou J (2011) Dimethylenastron suppresses human pancreatic cancer cell migration and invasion in vitro via allosteric inhibition of mitotic kinesin Eg5. Acta Pharmacol Sin 32:1543–1548CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Ludovica Taglieri
    • 1
  • Giovanna Rubinacci
    • 2
  • Anna Giuffrida
    • 1
  • Simone Carradori
    • 3
  • Susanna Scarpa
    • 1
    Email author
  1. 1.Department of Experimental MedicineSapienza UniversityRomeItaly
  2. 2.Department of Molecular MedicineSapienza UniversityRomeItaly
  3. 3.Department of Pharmacy“G. D’Annunzio” University of Chieti-PescaraChietiItaly

Personalised recommendations