title: In vitro targeting of Polo-like kinase 1 in bladder carcinoma: comparative effects of four potent inhibitors.
abstract: Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G 2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and pre-clinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs.
authors.affiliation: Division of Pediatric Oncology, Department of Pediatrics, University of São Paulo, São Paulo, Brazil. marsol@rge.fmrp.usp.br
authors.forename: María Sol
authors.initials: MS
authors.lastname: Brassesco
authors.forename: Julia Alejandra
authors.initials: JA
authors.lastname: Pezuk
authors.forename: Andressa Gois
authors.initials: AG
authors.lastname: Morales
authors.forename: Jaqueline Carvalho
authors.initials: JC
authors.lastname: de Oliveira
authors.forename: Gabriela Molinari
authors.initials: GM
authors.lastname: Roberto
authors.forename: Glenda Nicioli
authors.initials: GN
authors.lastname: da Silva
authors.forename: Harley
authors.initials: H
authors.lastname: Francisco de Oliveira
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Scrideli
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: Tone
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
keywords: PLK1 inhibition; bladder cancer; cell lines