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Cancer Chemotherapy and Pharmacology

, Volume 59, Issue 2, pp 157–164 | Cite as

Inhibitors of kinesin Eg5: antiproliferative activity of monastrol analogues against human glioblastoma cells

  • Christine Müller
  • Dietmar Gross
  • Vasiliki Sarli
  • Michael Gartner
  • Athanassios Giannis
  • Günther Bernhardt
  • Armin Buschauer
Original Article

Abstract

The inhibition of kinesin Eg5 by small molecules such as monastrol is currently evaluated as an approach to develop a novel class of antiproliferative drugs for the treatment of malignant tumours. Therefore, we studied the effects of the new monastrol analogues enastron, dimethylenastron and vasastrol VS-83 on the proliferation of human glioblastoma cells in the kinetic crystal violet assay. Compared to monastrol, the new cell cycle specific compounds showed an at least one order of magnitude higher anti proliferative activity against U-87 MG, U-118 MG, and U-373 MG glioblastoma cells. The compounds were neither inactivated by hydrolysis nor by binding to serum proteins. Moreover, we demonstrated the characteristic monoaster formation after incubation of cells with the new compounds by confocal laser scanning microscopy. We also showed that the arrangement of β-actin and tubulin, vital components of the cyto-skeleton of mitotic and quiescent cells, were not affected by the new compounds. Due to the necessity of overcoming the blood–brain barrier in the treatment of brain tumours, we investigated if the new monastrol analogues are modulators or substrates of the p-glycoprotein (p-gp) 170 by a flow cytometric calcein-AM efflux assay. The tested compounds showed no modulating effects on the p-gp function. With respect to the treatment of primary and secondary CNS tumours, the results of our experiments suggest that the new monastrol analogues represent an interesting class of potential anticancer drugs, predicted to be less neurotoxic in comparison to classical tubulin inhibitors.

Keywords

Kinesin inhibitors Monastrol analogues Human glioblastoma cells Chemosensitivity Confocal microscopy 

Notes

Acknowledgements

This work was supported by Grant MRTN CT-2004-512348 (Spindle Dynamics) from the European Commission. We also thank the Fonds der Chemischen Industrie for financial support.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Christine Müller
    • 1
  • Dietmar Gross
    • 1
  • Vasiliki Sarli
    • 2
  • Michael Gartner
    • 2
  • Athanassios Giannis
    • 2
  • Günther Bernhardt
    • 1
  • Armin Buschauer
    • 1
  1. 1.Institute of PharmacyUniversity of RegensburgRegensburgGermany
  2. 2.Institute of Organic ChemistryUniversity of LeipzigLeipzigGermany

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