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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Chuize Kong, Zhe Zhang, and Guo-Jun Zhang
- Subjects
0301 basic medicine ,Programmed cell death ,Mice, Nude ,Mitosis ,Apoptosis ,Cell Cycle Proteins ,Biology ,Protein Serine-Threonine Kinases ,Small Molecule Libraries ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Mitotic catastrophe ,Protein Kinase Inhibitors ,mitotic catastrophe ,Mice, Inbred BALB C ,Bladder cancer ,Cell growth ,Cancer ,RO3280 ,Epithelial Cells ,Cell Biology ,Original Articles ,Cell cycle ,medicine.disease ,Molecular biology ,Xenograft Model Antitumor Assays ,Wee1 ,030104 developmental biology ,cell death ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Molecular Medicine ,Female ,Original Article ,cell cycle ,PLK1 - 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.
- Published
- 2016