RETRACTED ARTICLE: The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

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 d...

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Bibliographic Details
Published in:Investigational new drugs 2016-08, Vol.34 (4), p.399-406
Main Authors: De Iuliis, Francesca, Taglieri, Ludovica, Salerno, Gerardo, Giuffrida, Anna, Milana, Bernardina, Giantulli, Sabrina, Carradori, Simone, Silvestri, Ida, Scarpa, Susanna
Format: Article
Language:English
Subjects:
AKT protein
Antiproliferatives
Antitumor activity
Apoptosis
Breast cancer
Cancer therapies
Cell cycle
Cell death
Chemoresistance
Clinical trials
Cytotoxicity
ErbB-2 protein
Estrogens
Inhibitors
Kinesin
Medical research
Medicine
Medicine & Public Health
Oncology
Overexpression
Pharmacology
Pharmacology/Toxicology
Phenotypes
Preclinical Studies
Prostate cancer
Protein structure
Proteins
Studies
Survival
Survivin
Tumor cell lines
Tumor cells
Tumors
Wortmannin
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Summary: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.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-016-0345-8