title: An in-vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies.
abstract: Polo-like kinase 1 (PLK1) is a regulator of mitosis and its upregulation in tumours is often associated with poor prognosis. Although PLK1 inhibitors have already entered phase 1 clinical trials, little is known about their impact on the treatment of paediatric malignancies. Thus, we evaluated the concept of PKL1 inhibition by testing the effects of the PLK1 inhibitor GW843682X alone and in combination with the topoisomerase 1 inhibitor, camptothecin, against a panel of 18 paediatric tumour cell lines. Cytotoxicity was evaluated by MTT test and by caspase 3/7 activation. Expression of target was confirmed by western blot analysis. Expression of ATP binding cassette transporters was analysed by quantitative real-time reverse transcription PCR. GW843682X significantly inhibited cell growth in all 18 cell lines. Concentrations, which inhibited cell growth by 50% compared with untreated controls after 72 h, ranged from 0.02 to 11.7 μmol/l. Apart from the N-Myc-amplified neuroblastoma cell lines, the osteosarcoma cell lines MNNG-HOS and OST, which are highly resistant to standard anticancer drugs, were sensitive to GW843682X. The toxicity of GW843682X was dependent neither on the ATP binding cassette drug transporter expression nor on the p53 mutation status. Neither synergistic nor antagonistic effects were observed for the combination of GW843682X and camptothecin in 14 cell lines. GW843682X showed considerable toxicity against a panel of paediatric tumour cell lines suggesting that PLK1 inhibitors under clinical development should be evaluated against paediatric malignancies too.
authors.affiliation: Department of Paediatric Haematology and Oncology, University Children's Hospital, Muenster, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Spaniol
authors.forename: Joachim
authors.initials: J
authors.lastname: Boos
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanvers-Kaminsky
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D004396:Coloring Agents; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013778:Tetrazolium Salts; D013844:Thiazoles; D013876:Thiophenes / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002166:Camptothecin; D020169:Caspases; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D013876:Thiophenes; D059004:Topoisomerase I Inhibitors; D000097869:Polo-Like Kinase 1; C524135:5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-((2-(trifluoromethyl)benzyl)oxy)thiophene-2-carboxamide; C022616:thiazolyl blue