Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance

• Published in: Investigational new drugs 2014-12, Vol.32 (6), p.1167-1180
• Main Authors: Sero, Valeria, Tavanti, Elisa, Vella, Serena, Hattinger, Claudia Maria, Fanelli, Marilù, Michelacci, Francesca, Versteeg, Rogier, Valsasina, Barbara, Gudeman, Beth, Picci, Piero, Serra, Massimo
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B - genetics; Biological and medical sciences; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Cancer therapies; Cell cycle; Cell Cycle - drug effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Diseases of the osteoarticular system; Doxorubicin - pharmacology; Drug Interactions; Drug resistance; Drug Resistance, Neoplasm - drug effects; Gene expression; Gene Expression Profiling; Humans; Kinases; Laboratories; Medical sciences; Medicine; Medicine & Public Health; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Orthopedics; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - metabolism; Pharmaceutical sciences; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polo-Like Kinase 1; Preclinical Studies; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyrazoles - pharmacology; Quinazolines - pharmacology; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Studies; Toxicity; Tumors; Tumors of striated muscle and skeleton
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0158-6

Summary 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.