Title:PLK1 Inhibition Radiosensitizes Breast Cancer Cells, but Shows Low Efficacy as Monotherapy or in Combination with other Cytotoxic Drugs
VOLUME: 18 ISSUE: 9
Author(s):María Sol Brassesco*, Julia Alejandra Pezuk, Karina Bezerra Salomão, Gabriela Molinari Roberto, Carlos Alberto Scrideli and Luiz Gonzaga Tone
Affiliation:Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Department of Genetics Ribeirao Preto School of Medicine, University of Sao Paulo, Department of Genetics Ribeirao Preto School of Medicine, University of Sao Paulo, Regional Blood Center of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Department of Pediatrics, Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo, Department of Pediatrics, Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo
Keywords:Breast, carcinoma, chemotherapy, drug, PLK1, radiotherapy.
Abstract:Background and Purpose: Over the last decade, the inhibition of PLK1 has proven potent antiproliferative
activity in vitro. However, the effectiveness of most synthetic targeted drugs has not yet been
translated into clinics. Herein, we investigated the in vitro effects of two second-generation PLK1 inhibitors BI
6727 and GSK461364 in breast cancer cell lines as monotherapy or in combination with other drugs or ionizing
radiation.
Material and Methods: Cell survival was analyzed through XTT®, clonogenicity and caspase-3 activation assays
were also studied, and drug interactions analyzed through a nonlinear regression of a sigmoid doseresponse
model. Sensibilization to radiation was assessed through enhancement ratio calculation.
Results: Mild effects on the viability of both cell lines tested (MCF-7 and Hs578T) were observed irrespective
of the used PLK1 inhibitor. Alternatively, abrogation of PLK1 significantly reduced clonogenicity while effectively
sensitized cells to ionizing radiation. Drug interactions showed dissimilar results with antagonistic effects
with any drug combination in MCF-7 and clear synergic interactions between both PLK1 inhibitors and cisplatin,
temozolomide or doxorubicin in Hs578T, which is TP53 mutated.
Conclusion: Targeting kinases involved in mitotic checkpoints are expected to prevent mitotic exit and enhance
chemosensitization. Nonetheless, despite overexpressing PLK1, in our model, expressive results after its inhibition
were only seen through clonogenic assays or when BI 6727 and GSK461364 were combined with ionizing
radiation. Disparate responses of cell lines to drug combinations might denote a partial reflection of the substantial
differences in the vast spectrum of genetic, biological and epigenetic burden observed in breast cancer. In
the near future, individual genomic/proteomic profiling will allow its further classification and will consent the
initiation of novel strategies for therapy. Even though the future impact of PLK1-tailored treatment still needs
validation, much more pre-clinical and clinical research for this kinase are warranted.
