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

Media type: E-Article

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

Contributor: 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]

Published: 16 July 2022

Language: English

DOI: 10.3390/ijms23147850

Identifier:

Keywords: Bcl-2 ; Bcl-x<sub>L</sub> ; cell death ; head and neck squamous cell carcinoma ; Mc-1 ; non-small-cell lung cancer ; radiotherapy ; synovial sarcoma ; therapy resistance

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Footnote:

Description: 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.

Access State: Open Access

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