title: Targeted inhibition of Polo-like kinase 1 by a novel small-molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells.
abstract: Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. Despite improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little. In this study, the anti-tumour activities of a novel Polo-like kinase 1 (PLK1) inhibitor (RO3280) was evaluated in vitro and in vivo in the bladder carcinoma cell lines 5637 and T24. MTT assays, colony-formation assays, flow cytometry, cell morphological analysis and trypan blue exclusion assays were used to examine the proliferation, cell cycle distribution and apoptosis of bladder carcinoma cells with or without RO3280 treatment. Moreover, real-time RT-PCR and Western blotting were used to detect the expressions of genes that are related to these cellular processes. Our results showed that RO3280 inhibited cell growth and cell cycle progression, increased Wee1 expression and cell division cycle protein 2 phosphorylation. In addition, RO3280 induced mitotic catastrophe and apoptosis, increased cleaved PARP (poly ADP-ribose polymerase) and caspase-3, and decreased BubR1 expression. The in vivo assay revealed that RO3280 retarded bladder cancer xenograft growth in a nude mouse model. Although further laboratory and pre-clinical investigations are needed to corroborate these data, our demonstration of bladder cancer growth inhibition and dissemination using a pharmacological inhibitor of PLK1 provides new opportunities for future therapeutic intervention.
authors.affiliation: Department of Urology, The First Hospital of China Medical University, Shenyang City, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shengjing Hospital of China Medical University, Shenyang City, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Urology, The First Hospital of China Medical University, Shenyang City, China.
authors.forename: Chuize
authors.initials: C
authors.lastname: Kong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D000097869:Polo-Like Kinase 1
keywords: PLK1; RO3280; cell cycle; cell death; mitotic catastrophe