title: Inhibitors of kinesin Eg5: antiproliferative activity of monastrol analogues against human glioblastoma cells.
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 beta-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.
authors.affiliation: Institute of Pharmacy, University of Regensburg, Universitätsstrasse 31, 93040, Regensburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Müller
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gross
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Sarli
authors.forename: Michael
authors.initials: M
authors.lastname: Gartner
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000166:Acridines / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D005452:Fluoresceins / Q000494:pharmacology; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007306:Insecticides / Q000494:pharmacology; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000972:Antineoplastic Agents, Phytogenic; D005452:Fluoresceins; D007306:Insecticides; C470243:KIF11 protein, human; D011743:Pyrimidines; D011799:Quinazolines; D044005:Tetrahydroisoquinolines; D013871:Thiones; D014404:Tubulin; D050257:Tubulin Modulators; C518969:dimethylenastron; C518968:enastron; C518970:vasastrol VS-83; D012402:Rotenone; C085925:calcein AM; C003724:3-tritylthio-L-alanine; D014747:Vinblastine; C400223:monastrol; D016547:Kinesins; D003545:Cysteine; C083501:Elacridar; D017239:Paclitaxel