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

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Summary

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.

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Authors and Affiliations

  1. Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy

    Francesca De Iuliis, Ludovica Taglieri, Gerardo Salerno, Anna Giuffrida, Bernardina Milana & Susanna Scarpa

  2. Department of Molecular Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy

    Sabrina Giantulli & Ida Silvestri

  3. Department of Pharmacy, “G. D’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy

    Simone Carradori

Authors
  1. Francesca De Iuliis
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  2. Ludovica Taglieri
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  3. Gerardo Salerno
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  4. Anna Giuffrida
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  9. Susanna Scarpa
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Correspondence to Susanna Scarpa.

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De Iuliis, F., Taglieri, L., Salerno, G. et al. The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells. Invest New Drugs 34, 399–406 (2016). https://doi.org/10.1007/s10637-016-0345-8

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  • DOI: https://doi.org/10.1007/s10637-016-0345-8

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