Inhibitors of kinesin Eg5: antiproliferative activity of monastrol analogues against human glioblastoma cells
- 442 Downloads
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.
KeywordsKinesin inhibitors Monastrol analogues Human glioblastoma cells Chemosensitivity Confocal microscopy
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.
- 14.Hubensack M (2005) Approaches to overcome the blood–brain barrier in the chemotherapy of primary and secondary brain tumors: modulation of P-glycoprotein 170 and targeting of the transferrin receptor. Doctoral thesis, University of Regensburg, http://www.opus-bayern.de/uni-regensburg/volltexte/2005/471/
- 18.Tarby CM, Kaltenbach RF, III, Huynh T, Pudzianowski A, Shen H, Ortega-Nanos M, Sheriff S, Newitt JA, McDonnel PA, Burford N, Fairchild CR, Vaccaro W, Chen Z, Borzilleri RM, Naglich J, Lombardo LJ, Gottardis M, Trainor GL, Roussel DL (2006) Inhibitors of human mitotic kinesin Eg5: characterization of the 4-phenyl-tetrahydroisoquinoline lead series. Bioorg Med Chem Lett 16:2095–2100PubMedCrossRefGoogle Scholar