1. Targeted inhibition of Polo-like kinase 1 by a novel small-molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells.
- Author
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Zhang Z, Zhang G, and Kong C
- Subjects
- Animals, Cell Cycle Proteins metabolism, Cell Line, Tumor, Epithelial Cells drug effects, Epithelial Cells metabolism, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Xenograft Model Antitumor Assays, Polo-Like Kinase 1, Apoptosis drug effects, Cell Cycle Proteins antagonists & inhibitors, Mitosis drug effects, Molecular Targeted Therapy, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Small Molecule Libraries pharmacology, Urinary Bladder Neoplasms enzymology, Urinary Bladder Neoplasms pathology
- 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., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Published
- 2017
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