The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and the current chemotherapeutic options for GBM are limited to temozolomide. Recently, inhibitors of kinesin spindle protein Eg5 have shown pronounced antitumor activity and our group has demonstrated that one of these inhibitors of kinesin Eg5, named K858, exerts important anti-proliferative and apoptotic effects on breast cancer cells. Since GBM cells usually express high levels of kinesin Eg5, we tested the effect of K858 on two human GBM cell lines (U-251 and U-87) and found that K858 could inhibit cell growth, induce apoptosis, revert epithelial-mesenchymal transition and inhibit migration in both cell lines. However, at the same time, K858 increased survivin expression, an anti-apoptotic molecule; so, down-regulating survivin with the specific inhibitor YM155, we obtained an important increase of K858-dependent apoptosis. This indicated that the anti-tumor activity of K858 on GBM was limited by the over-expression of survivin and that the negative regulation of this protein could sensitize tumor cells to K858-induced apoptosis. These data support the choice of kinesin Eg5 as target of new therapeutic approaches for GBM; in particular, K858 has been demonstrated to be a potent inhibitor of replication, inducer of apoptosis and negative regulator of the invasive phenotype for GBM cells.