title: Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Experimental Oncology, Rizzoli Orthopaedic Institute, Via di Barbiano 1/10, 40136, Bologna, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Sero
authors.forename: Elisa
authors.initials: E
authors.lastname: Tavanti
authors.forename: Serena
authors.initials: S
authors.lastname: Vella
authors.forename: Claudia Maria
authors.initials: CM
authors.lastname: Hattinger
authors.forename: Marilù
authors.initials: M
authors.lastname: Fanelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Michelacci
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Beth
authors.initials: B
authors.lastname: Gudeman
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004317:Doxorubicin; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C513055:ABCB1 protein, human; C560415:NMS P937