Microtubules are dynamic polymers involved in a multitude of cellular processes. Indibulin is a small-molecule microtubule inhibitor that exhibits antitumor activity but does not cause neurotoxicity. Indibulin dose-dependently inhibited the polymerization of purified calf brain tubulin with an IC50 value of ~0.25μM and a maximal inhibition of 90%. [1] Indibulin inhibited the proliferation of MCF-7 cells with an IC50 value of 150 ± 13nM. Cells treated with 600nM indibulin showed an increased percentage of phosphohistone H3 (S10) compared to the control group. The disruption of the microtubule network was observed when MCF-7 cells were treated with 300nM indibulin. In cells incubated with 600nM indibulin, most of the microtubules were depolymerized compared to the control group. The rates of growth and shortening states of microtubules in MCF-7 cells were reduced by 37 and 53%, respectively, in the presence of 150nM indibulin. Treatment of MCF-7 cells with indibulin (300 and 600nM) increased the levels of Mad2 and BubR1 and activated apoptotic cell death. The combination of indibulin (50 and 150nM) and 1nM vinblastine inhibited the proliferation of MCF-7 cells by 53 and 71%, respectively.[2] In a rat Yoshida AH13 sarcoma model, administration of indibulin (10mg/kg, p.o.) for two weeks resulted in complete tumor remissions.[3]
作用机制
Indibulin is a synthetic inhibitor of tubulin assembly that inhibits microtubule dynamics by blocking mitosis.[2]
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