TY  - JOUR
A1  - Hehlgans, Stephanie
A1  - Booms, Patrick
A1  - Güllülü, Ömer
A1  - Sader, Robert Alexander
A1  - Rödel, Claus
A1  - Balermpas, Panagiotis
A1  - Rödel, Franz
A1  - Ghanaati, Shahram Michael
T1  - Radiation sensitization of basal cell and head and neck squamous cell carcinoma by the hedgehog pathway inhibitor vismodegib
T2  - International journal of molecular sciences
N2  - 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.
KW  - basal cell carcinoma
KW  - head and neck squamous cell carcinoma
KW  - hedgehog signaling pathway
KW  - radiotherapy resistance
KW  - vismodegib (GDC-0449)
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47360
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-473600
SN  - 1422-0067
SN  - 1661-6596
N1  - 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).
VL  - 19
IS  - 9, Art. 2485
SP  - 1
EP  - 15
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -