Radiation sensitization of basal cell and head and neck squamous cell carcinoma by the hedgehog pathway inhibitor vismodegib

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 radiatio
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.
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Metadaten
Author:Stephanie Hehlgans, Patrick Booms, Ömer Güllülü, Robert Alexander Sader, Claus Rödel, Panagiotis Balermpas, Franz Rödel, Shahram Ghanaati
URN:urn:nbn:de:hebis:30:3-473600
DOI:http://dx.doi.org/10.3390/ijms19092485
ISSN:1422-0067
ISSN:1661-6596
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=30142876
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/08/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/11/01
Tag:basal cell carcinoma; head and neck squamous cell carcinoma; hedgehog signaling pathway; radiotherapy resistance; vismodegib (GDC-0449)
Volume:19
Issue:9, Art. 2485
Pagenumber:15
First Page:1
Last Page:15
Note:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
HeBIS PPN:439985188
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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