Abstract
IntroductionSeveral kinase inhibitors (KI) bear the potential to act as radiosensitizers. Little is known of the radiosensitizing effects of a wide range of other KI like palbociclib, which is approved in ER+/HER2- metastatic breast cancer.MethodIn our study, we used healthy donor fibroblasts and breast cancer and skin cancer cells to investigate the influence of a concomitant KI + radiation therapy. Cell death and cell cycle distribution were studied by flow cytometry after Annexin-V/7-AAD and Hoechst staining. Cellular growth arrest was studied in colony-forming assays. Furthermore, we used C12-FDG staining (senescence) and mRNA expression analysis (qPCR) to clarify cellular mechanisms.ResultsThe CDK4/6 inhibitor palbociclib induced a cell cycle arrest in the G0/G1 phase. Cellular toxicity (cell death) was only slightly increased by palbociclib and not enhanced by additional radiotherapy. As the main outcome of the colony formation assays, we found that cellular growth arrest was induced by palbociclib and improved by radiotherapy in an additive manner. Noticeably, palbociclib treatment clearly induced senescence not only in breast cancer and partly in melanoma cells, but also in healthy fibroblasts. According to these findings, the downregulation of senescence-related FOXM1 might be an involved mechanism of the senescence-induction potential of palbociclib.ConclusionThe effect on cellular growth arrest of palbociclib and radiotherapy is additive. Palbociclib induces permanent G0/G1 cell cycle arrest by inducing senescence in fibroblasts, breast cancer, and melanoma cells. Direct cell death induction is only a minor secondary mechanism of action. Concomitant KI and radiotherapy is a strategy worth studying in clinical trials.
Highlights
Several kinase inhibitors (KI) bear the potential to act as radiosensitizers
As the main outcome of the colony formation assays, we found that cellular growth arrest was induced by palbociclib and improved by radiotherapy in an additive manner
Human skin fibroblasts SBLF7 and SBLF9 derived from different healthy donors; melanoma cells LIWE, HV18MK, ICNI, RERO, ARPA, and ANST derived from different malign melanoma patients; and breast cancer cell lines MDA-MB-231 (TNBC) and MCF-7 (ER+, Progesterone receptor (PR)+) were used
Summary
Little is known of the radiosensitizing effects of a wide range of other KI like palbociclib, which is approved in ER+/HER2- metastatic breast cancer. Citing the European Cancer Information System (ECIS), over 355,000 women in the EU-27 are estimated to be diagnosed with breast cancer in 2020 [1]. This represents 13.3% of all cancer diagnoses. Palbociclib is a kinase inhibitor (KI) that blocks the cell cycle by inhibiting the phosphorylation of the Rb protein and was approved by the European Medicines Agency (EMA) in 2016 for ER+ and HER2metastatic breast cancer [3]. The question of combining different therapy options like concomitant radiotherapy (RT) with focus on radiosensitization arises [4], especially in the metastatic situation, since metastases are commonly treated with irradiation [5]
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