The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells
- 254 Downloads
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.
KeywordsGlioblastoma 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.
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent was obtained from all individual participants included in this study.
- 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
- 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
- 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. https://doi.org/10.18632/oncotarget.18337
- 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.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
- 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