Pharmaceutically inhibiting polo‐like kinase 1 exerts a broad anti‐tumour activity in retinoblastoma cell lines

Abstract Background Retinoblastoma is the most common malignant cancer of the eye in children. Although metastatic retinoblastoma is rare, cure rates for this advanced disease remain below 50%. High‐level polo‐like kinase 1 expression in retinoblastomas has previously been shown to be correlated with adverse outcome parameters. Polo‐like kinase 1 is a serine/threonine kinase involved in cell cycle regulation at the G2/M transition. Polo‐like kinase 1 inhibition has been demonstrated to have anti‐tumour effects in preclinical models of several paediatric tumours. Here, we assessed its efficacy against retinoblastoma cell lines. Methods Expression of polo‐like kinase 1 was determined in a panel of retinoblastoma cell lines by polymerase chain reaction and western blot analysis. We analysed viability (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) (MTT assay), proliferation (5‐bromo‐2'‐deoxyuridine enzyme‐linked immunosorbent assay), cell cycle progression (propidium iodid staining) and apoptosis (cell death enzyme‐linked immunosorbent assay) in three retinoblastoma cell lines after treatment with two adenosine triphosphate‐competitive polo‐like kinase 1 inhibitors, BI6727 or GSK461364. Activation of polo‐like kinase 1 downstream signalling components including TP53 were assessed. Results Treatment of retinoblastoma cells with either BI6727 or GSK461364 reduced cell viability and proliferative capacity and induced both cell cycle arrest and apoptosis. Polo‐like kinase 1 inhibition also induced the p53 signalling pathway. Analysis of key players in cell cycle control revealed that low nanomolar concentrations of either polo‐like kinase 1 inhibitor upregulated cyclin B1 and increased activated cyclin‐dependent kinase 1 (phosphorylated at Y15) in retinoblastoma cell lines. Conclusions These preclinical data indicate that polo‐like kinase 1 inhibitors could be useful as components in rationally designed chemotherapy protocols to treat patients with metastasized retinoblastoma in early phase clinical trials.