Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors
In: International Journal of Molecular Sciences; Volume 23; Issue 14; Pages: 7850, 2022
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Zugriff:
Avoidance of therapy-induced apoptosis is a hallmark of acquired resistance towards radiotherapy. Thus, breaking resistance still challenges modern cancer therapy. The Bcl-2 protein family is known for its regulatory role in apoptosis signaling, making Bcl-2, Mcl-1 and Bcl-xL promising targets. This study evaluates the effects of highly specific inhibitors for Bcl-xL (WEHI-539), Bcl-2 (ABT-199) and Mcl-1 (S63845) as radiosensitizers. Covering a broad spectrum of solid tumors, Non-Small-Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC) and synovial sarcoma cell lines were exposed to fractionated radiation as standard therapy with or without Bcl-2 protein inhibition. Protein expression was detected by Western blot and cell death was assessed by flow cytometry measuring apoptosis. In contrast to NSCLC, a high level of Bcl-xL and its upregulation during radiotherapy indicated radioresistance in HNSCC and synovial sarcoma. Radioresistant cell lines across all entities benefited synergistically from combined therapy with Bcl-xL inhibition and fractionated radiation. In NSCLC cell lines, Mcl-1 inhibition significantly augmented radiotherapy independent of the expression level. Our data suggest that among antiapoptotic Bcl-2 proteins, targeting Bcl-xL may break resistance to radiation in HNSCC, synovial sarcoma and NSCLC in vitro. In NSCLC, Mcl-1 might be a promising target that needs further investigation.
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Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors
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Autor/in / Beteiligte Person: | Sobol, Benjamin ; Osama Azzam Nieto ; Emily Lara Eberlein ; Scherr, Anna-Lena ; Ismail, Lars ; Kessler, Annika ; Nader, Luisa ; Schwab, Maximilian ; Hoffmeister, Paula ; Schmitt, Nathalie ; Jäger, Dirk ; Welte, Stefan ; Seidensaal, Katharina ; Christopoulos, Petros ; Heilig, Christoph ; Kriegsmann, Katharina ; Fröhling, Stefan ; Kriegsmann, Mark ; Hess, Jochen ; Bruno Christian Köhler |
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Zeitschrift: | International Journal of Molecular Sciences; Volume 23; Issue 14; Pages: 7850, 2022 |
Veröffentlichung: | Multidisciplinary Digital Publishing Institute, 2022 |
Medientyp: | academicJournal |
DOI: | 10.3390/ijms23147850 |
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