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Open AccessArticle

Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib

1
Department of Radiotherapy and Oncology, Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, Germany
2
Department for Oral, Cranio-Maxillofacial and Facial Plastic Surgery, Frankfurt Orofacial Regenerative Medicine (FORM), Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(9), 2485; https://doi.org/10.3390/ijms19092485
Received: 10 August 2018 / Accepted: 21 August 2018 / Published: 23 August 2018
(This article belongs to the Special Issue Advances and Challenges in Biomolecular Radiation Research)
Vismodegib, an inhibitor of the Hedgehog signaling pathway, is an approved drug for monotherapy in locally advanced or metastatic basal cell carcinoma (BCC). Data on combined modality treatment by vismodegib and radiation therapy, however, are rare. In the present study, we examined the radiation sensitizing effects of vismodegib by analyzing viability, cell cycle distribution, cell death, DNA damage repair and clonogenic survival in three-dimensional cultures of a BCC and a head and neck squamous cell carcinoma (HNSCC) cell line. We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells. Furthermore, vismodegib significantly reduced proliferation in both cell lines, while additional irradiation only slightly further impacted on viability. Analyses of cell cycle distribution and cell death induction indicated a G1 arrest in BCC and a G2 arrest in HNSCC cells and an increased fraction of cells in SubG1 phase following combined treatment. Moreover, a significant rise in the number of phosphorylated histone-2AX/p53-binding protein 1 (γH2AX/53BP1) foci in vismodegib- and radiation-treated cells was associated with a significant radiosensitization of both cell lines. In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells. View Full-Text
Keywords: basal cell carcinoma; head and neck squamous cell carcinoma; hedgehog signaling pathway; radiotherapy resistance; vismodegib (GDC-0449) basal cell carcinoma; head and neck squamous cell carcinoma; hedgehog signaling pathway; radiotherapy resistance; vismodegib (GDC-0449)
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Hehlgans, S.; Booms, P.; Güllülü, Ö.; Sader, R.; Rödel, C.; Balermpas, P.; Rödel, F.; Ghanaati, S. Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib. Int. J. Mol. Sci. 2018, 19, 2485.

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