gms | German Medical Science

69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

03.06. - 06.06.2018, Münster

Article

Send article

KIF11 inhibitors Filanesib and Ispinesib as novel small molecule inhibitors for meningioma therapy

Meeting Abstract

Search Medline for

  • Gerhard Jungwirth - Ruprecht-Karls-Universität, Division of Experimental Neurosurgery, Heidelberg, Deutschland
  • Christine Jungk - Ruprecht-Karls-Universität, Division of Experimental Neurosurgery, Heidelberg, Deutschland
  • Rolf Warta - Ruprecht-Karls-Universität, Division of Experimental Neurosurgery, Heidelberg, Deutschland
  • Christel Herold-Mende - Ruprecht-Karls-Universität, Division of Experimental Neurosurgery, Heidelberg, Deutschland
  • Andreas W. Unterberg - Ruprecht-Karls-Universität, Division of Experimental Neurosurgery, Heidelberg, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie. Münster, 03.-06.06.2018. Düsseldorf: German Medical Science GMS Publishing House; 2018. DocV016

doi: 10.3205/18dgnc017, urn:nbn:de:0183-18dgnc0174

Published: June 18, 2018

© 2018 Jungwirth et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Objective: KIF11 is a highly conserved motor protein, which plays an important role in cell division by separating the spindle poles. KIF11 has been reported to be involved in multiple cancer types including melanoma, retinoblastoma, and glioma. Previously, we found a tumor grade-specific elevated mRNA and protein expression of KIF11 in meningioma. Higher levels of KIF11 were associated with shorter progression-free survival by only including gross total resection and treatment-naïve tumors. Additionally, siRNA mediated knockdown inhibited the proliferation of meningioma cell lines in vitro. Since small molecule KIF11 inhibitors such as Filanesib and Ispinesib are currently tested in clinical trials for other tumor types, we sought to investigate a potential benefit for the treatment of meningiomas.

Methods: Filanesib and Ispinesib are small molecule inhibitors for KIF11. Cell proliferation assay was done by crystal violet assay or manual counting. Scratch assay was performed with 100 nM of Ispinesib or Filanesib or DMSO as control. Pictures were taken 4, 8 and 12 hours after treatment. All experiments were performed in triplicate. Statistical analyses were performed in Graph Pad Prism.

Results: Dose-curve analysis of Filanesib and Ispinesib by crystal violet assay revealed IC50 values of less than 1 nM in the benign meningioma cell line Ben-Men-1 and the anaplastic cell line NCH93. Inhibitor dosage of 10 nM and higher lead to an average inhibition of Ben-Men-1 cells of 58% and 66% on day 1 and 2 for Filanesib and by 63% and 60% for Ispinesib, respectively. Proliferation of NCH93 cells was decreased by 63% and 84% for Filanesib and by 67% and 89% for Ispinesib (p<.001). Furthermore, when performing scratch assays treatment with Filanesib and Ispinesib lead to a reduced migration in NCH93 cells after 8 and 12 hours (p<.05). Currently, we are testing these KIF11 inhibitors in combination with radiation in a xenograft mouse model.

Conclusion: Taken together, KIF11 inhibitors Filanesib and Ispinesib could play an important role in future meningioma therapy.