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Specific targeting of antiapoptotic Bcl-2 proteins as a radiosensitizing approach in solid tumors

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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...

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Main Authors: Sobol, Benjamin (Author) , Azzam Nieto, Osama (Author) , Eberlein, Emily Lara (Author) , Scherr, Anna-Lena (Author) , Ismail, Lars (Author) , Keßler, Annika (Author) , Nader, Luisa (Author) , Schwab, Maximilian (Author) , Hoffmeister-Wittmann, Paula (Author) , Schmitt, Nathalie (Author) , Jäger, Dirk (Author) , Welte, Stefan Ezechiel (Author) , Seidensaal, Katharina (Author) , Christopoulos, Petros (Author) , Heilig, Christoph E. (Author) , Kriegsmann, Katharina (Author) , Fröhling, Stefan (Author) , Kriegsmann, Mark (Author) , Heß, Jochen (Author) , Köhler, Bruno Christian (Author)
Format: Article (Journal)
Language:English
Published: 16 July 2022
In: International journal of molecular sciences
Year: 2022, Volume: 23, Issue: 14, Pages: 1-13
ISSN:1422-0067
DOI:10.3390/ijms23147850
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.3390/ijms23147850
Verlag, kostenfrei, Volltext: https://www.mdpi.com/1422-0067/23/14/7850
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Author Notes:Benjamin Sobol, Osama Azzam Nieto, Emily Lara Eberlein, Anna-Lena Scherr, Lars Ismail, Annika Kessler, Luisa Nader, Maximilian Schwab, Paula Hoffmeister, Nathalie Schmitt, Dirk Jäger, Stefan Welte, Katharina Seidensaal, Petros Christopoulos, Christoph Heilig, Katharina Kriegsmann, Stefan Fröhling, Mark Kriegsmann, Jochen Hess and Bruno Christian Köhler
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Summary: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.
Item Description:Gesehen am 19.08.2022
Physical Description:Online Resource
ISSN:1422-0067
DOI:10.3390/ijms23147850

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