Abstract | PURPOSE: METHODS AND MATERIALS: Clonogenic assays, immunoblotting, flow cytometry/fluorescence-activated cell sorting, and senescence assays were employed in liposarcoma cell lines after co-treatment with nutlin-3 and radiation. RESULTS: Upon treatment with nutlin-3, 2 of the well-/ dedifferentiated liposarcoma (MDM2Amp/TP53WT) cell lines displayed radiosensitivity with sensitization enhancement ratio values of >1. In contrast, the cell line with mutant TP53 showed sensitization enhancement ratio values of ∼1. Immunoblotting revealed induced reactivation of the p53-MDM2-p21 signaling axis in response to combination therapy in all cell lines with wild-type TP53. Removal of MDM2 inhibitor (with or without radiation therapy) led to the emergence of ploidy-based heterogeneous subpopulations (4N and >4N) in TP53 wild-type cells and not in TP53 mutant cells. Immunoblotting of cell cycle markers (G1, G2/M) revealed the generation of 4N G1 cells. Sorting and long-term fate analysis of different populations (2N, 4N, and >4N) by colony assay displayed attenuated colony-forming potential and augmented senescence of the 4N and >4N cells contributing to the radiosensitization effect. CONCLUSIONS:
Nutlin-3 increases the vulnerability of liposarcoma cell lines to radiation by augmented activation of p53. The cells underwent senescence. Presence and activation of p53 are required for exertion of the radiosensitizing effect by nutlin-3, but this is not the sole determinant of the effect. This study opens avenues for the clinical translation in a stratified group of patients with liposarcoma.
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Authors | Samayita Das |
Journal | Advances in radiation oncology
(Adv Radiat Oncol)
2020 Mar-Apr
Vol. 5
Issue 2
Pg. 250-259
ISSN: 2452-1094 [Print] United States |
PMID | 32280825
(Publication Type: Journal Article)
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Copyright | © 2019 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. |