Polo-Like Kinase 1 Pharmacological Inhibition as Monotherapy or in Combination: Comparative Effects of Polo-Like Kinase 1 Inhibition in Medulloblastoma Cells.

Abstract

Medulloblastoma (MB) is one of most frequent malignant tumors that affect children. Despite the relatively good survival rate, long time sequels still represent a challenge for MB. Therefore, in an attempt to reduce treatment aftereffects, new therapeutic targets are constantly being explored. Polo like kinase 1 (PLK1) is a master cell cycle regulator that is increased in proliferative cells, while its depletion has been repeatedly proposed as an oncological therapeutic strategy. Here, we evaluated and compared the effects of PLK1 inhibition alone and in combination with currently used radio- and chemotherapy in MB cells. UW402, UW473, ONS-76 and DAOY MB cell lines were treated with BI 2536, BI 6727, GW843682X, and GSK461364 PLK1 inhibitors and cell proliferation, apoptosis, clonogenicity, cell invasion, adhesion and cell cycle distribution were evaluated. In addition, the combinatorial effect with gamma irradiation or etoposide, cisplatin and temozolomide was evaluated. We show that PLK1 inhibition causes a significant decrease on cell proliferation, clonogenic capacity, cell invasion and adhesion, with modest differences between inhibitors. Yet, the four drugs cause G2/M arrest followed by increased cell death. PLK1 inhibition proved to be efficient to sensitize MB cells to radiation irrespective of the inhibitor, even though it showed thrifty results when combined with chemotherapy. We proved that all PLK1 inhibitors have anti-mitotic effects on MB cells, supporting the idea of using them as radiosensitizers. Taken together, our results strengthen the potential of using PLK1 as a therapeutic target to improve treatment strategy for this tumor.