Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance
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Background Polo-like kinase 1 (PLK1) has emerged as a prognostic factor in various neoplasms, but only scarce data have been reported for high-grade osteosarcoma (OS). In this study, we assessed PLK1 expression and the efficacy of PLK1 inhibitor NMS-P937 in OS. Methods PLK1 expression was assessed on 21 OS clinical samples and on a panel of human OS cell lines. In vitro efficacy of NMS-P937 was evaluated on nine drug-sensitive and six drug-resistant human OS cell lines, either as single agent or in combination with the drugs used in chemotherapy for OS. Results PLK1 expression was higher in OS clinical samples and cell lines compared to normal human tissue. A higher PLK1 expression at diagnosis appeared to be associated with an unfavourable clinical outcome. PLK1 silencing produced growth inhibition, cell cycle retardation and apoptosis induction in human OS cell lines. NMS-P937 proved to be highly active in both drug-sensitive and drug-resistant cell lines, with the only exception of ABCB1-overexpressing, Doxorubicin (DX)-resistant variants. However, in these cells, the association of NMS-P937 with DX was able to revert DX-resistance by negatively interfering with ABCB1 transport activity. NMS-P937 was also able to decrease clonogenic and migration ability of human OS cell lines. Conclusion PLK1 can be proposed as a new candidate target for OS. Targeting PLK1 in OS with NMS-P937 in association with conventional chemotherapeutic drugs may be a new interesting therapeutic option, since this approach has proved to be active against drug resistant cells.
KeywordsPolo-like kinase 1 Osteosarcoma Drug resistance NMS-P937 ABCB1 Novel therapeutic strategies
This study was supported by grants from: Associazione Italiana per la Ricerca sul Cancro (A.I.R.C., grant to Massimo Serra); Istituto Ortopedico Rizzoli (5‰ contributions to Rizzoli Institute); the European Project “Kids Cancer Kinome” (KCK; grant No.037390; http://www.kidscancerkinome.org/). Dr. Elisa Tavanti received a fellowship from the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.) for the research project “Pre-clinical validation of approaches targeting protein kinases in osteosarcoma”. We would like to thank Nerviano Medical Sciences (Nerviano, Italy) that kindly provided us NMS-P937 and CBA Research Inc. (Lexington, KY) that kindly provided us CBT-1. We also thank Dr. Peter van Sluis and Dr. Jan Koster (Academic Medical Center, University of Amsterdam, The Netherlands) for profiling data handling and assistance with R2 software. We would like to thank Dr. Alba Balladelli for editing the manuscript.
The Authors declare that all experiments were performed in compliance with Italian laws.
Conflict of interest
The Authors declare no conflict of interest. Nerviano Medical Sciences and CBA Research Inc. nor their affiliates provided any funding for this research.
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