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Volume 12
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10.3390/cancers12020467
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Article

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining

by
Ulrike Schötz
1,*,
Viola Balzer
1,
Friedrich-Wilhelm Brandt
1,
Frank Ziemann
1,
Florentine S.B. Subtil
1,
Thorsten Rieckmann
2,3,
Sabrina Köcher
2,
Rita Engenhart-Cabillic
1,
Ekkehard Dikomey
1,2,
Andrea Wittig
1,4,† and
Andrea Arenz
1,†
1
Department of Radiotherapy and Radiooncology, Philipps-University, University Hospital Giessen and Marburg, 35043 Marburg, Germany
2
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg Eppendorf, 20251 Hamburg, Germany
3
Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg Eppendorf, 20251 Hamburg, Germany
4
Department of Radiotherapy and Radiation Oncology, University Hospital-Jena, 07740 Jena, Germany
*
Author to whom correspondence should be addressed.
†
Shared last authorship.
Cancers 2020, 12(2), 467; https://doi.org/10.3390/cancers12020467
Received: 1 November 2019 / Revised: 27 January 2020 / Accepted: 7 February 2020 / Published: 18 February 2020
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Abstract

The PI3K/Akt/mTOR pathway is frequently altered in human papillomavirus (HPV)-positive and negative squamous cell carcinoma of the head and neck (HNSCC) and overstimulation is associated with poor prognosis. PI3K drives Akt activation and constitutive signaling acts pro-proliferative, supports cell survival, DNA repair, and contributes to radioresistance. Since the small molecule NVP-BEZ235 (BEZ235) is a potent dual inhibitor of this pathway, we were interested whether BEZ235 could be an efficient radiosensitizer. The 50 nM BEZ235 was found to abrogate endogenous and irradiation-induced phosphorylation of Akt (Ser473). The anti-proliferative capacity of the drug resulted in an increase in G1-phase cells. Repair of radiation-induced DNA double-strand breaks (DSBs) was strongly suppressed. Reduction in DSB repair was only apparent in G1- but not in G2-phase cells, suggesting that BEZ235 primarily affects non-homologous end joining. This finding was confirmed using a DSB repair reporter gene assay and could be attributed to an impaired phosphorylation of DNA-PKcs (S2056). Cellular radiosensitivity increased strongly after BEZ235 addition in all HNSCC cell lines used, especially when irradiated in the G0 or G1 phase. Our data indicate that targeting the PI3K/Akt/mTOR pathway by BEZ235 with concurrent radiotherapy may be considered an effective strategy for the treatment of HNSCC, regardless of the HPV and Akt status. View Full-Text
Keywords: radiation; radiosensitizer; radioresistance; HNSCC; Akt; DNA-PKcs; BEZ235 radiation; radiosensitizer; radioresistance; HNSCC; Akt; DNA-PKcs; BEZ235
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MDPI and ACS Style

Schötz, U.; Balzer, V.; Brandt, F.-W.; Ziemann, F.; Subtil, F.S.B.; Rieckmann, T.; Köcher, S.; Engenhart-Cabillic, R.; Dikomey, E.; Wittig, A.; Arenz, A. Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining. Cancers 2020, 12, 467. https://doi.org/10.3390/cancers12020467

AMA Style

Schötz U, Balzer V, Brandt F-W, Ziemann F, Subtil FSB, Rieckmann T, Köcher S, Engenhart-Cabillic R, Dikomey E, Wittig A, Arenz A. Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining. Cancers. 2020; 12(2):467. https://doi.org/10.3390/cancers12020467

Chicago/Turabian Style

Schötz, Ulrike, Viola Balzer, Friedrich-Wilhelm Brandt, Frank Ziemann, Florentine S.B. Subtil, Thorsten Rieckmann, Sabrina Köcher, Rita Engenhart-Cabillic, Ekkehard Dikomey, Andrea Wittig, and Andrea Arenz. 2020. "Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining" Cancers 12, no. 2: 467. https://doi.org/10.3390/cancers12020467

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