title: The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Iuliis
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Taglieri
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Salerno
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Giuffrida
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Bernardina
authors.initials: B
authors.lastname: Milana
authors.affiliation: Department of Molecular Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giantulli
authors.affiliation: Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.affiliation: Department of Molecular Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Silvestri
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy. susanna.scarpa@uniroma1.it.
authors.forename: Susanna
authors.initials: S
authors.lastname: Scarpa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000037:antagonists & inhibitors*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D000077022:Survivin; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C541942:K 858; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D013830:Thiadiazoles; D011065:Poly(ADP-ribose) Polymerases; C505530:CASP8 protein, human; D053181:Caspase 8; D053453:Caspase 9; D016547:Kinesins
keywords: Apoptosis; Breast cancer; Chemoresistance; K858; Kinesin inhibitor; Survivin