The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Inhibitors of Kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast Cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast Cancer cell line by inducing Apoptosis. However, at the same time, we showed that K858 up-regulated Survivin, an anti-apoptotic molecule. We then performed a negative regulation of Survivin expression, with the utilization of wortmannin, an Akt Inhibitor, and obtained a significant increase of K858-dependent Apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces Apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of Survivin levels, obtained with Akt inhibitors, can sensitize tumor cells to K858-induced Apoptosis.