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 radiation therapy, however, are rare. In the present study, we examined the radiation se...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2018-08-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | http://www.mdpi.com/1422-0067/19/9/2485 |
id |
doaj-4f99ca564cf749c592017a6328f4277c |
---|---|
record_format |
Article |
spelling |
doaj-4f99ca564cf749c592017a6328f4277c2020-11-25T01:02:16ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-08-01199248510.3390/ijms19092485ijms19092485Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor VismodegibStephanie Hehlgans0Patrick Booms1Ömer Güllülü2Robert Sader3Claus Rödel4Panagiotis Balermpas5Franz Rödel6Shahram Ghanaati7Department of Radiotherapy and Oncology, Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDepartment for Oral, Cranio-Maxillofacial and Facial Plastic Surgery, Frankfurt Orofacial Regenerative Medicine (FORM), Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDepartment of Radiotherapy and Oncology, Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDepartment for Oral, Cranio-Maxillofacial and Facial Plastic Surgery, Frankfurt Orofacial Regenerative Medicine (FORM), Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDepartment of Radiotherapy and Oncology, Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDepartment of Radiotherapy and Oncology, Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDepartment of Radiotherapy and Oncology, Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDepartment for Oral, Cranio-Maxillofacial and Facial Plastic Surgery, Frankfurt Orofacial Regenerative Medicine (FORM), Medical Center Goethe-University Frankfurt am Main, 60590 Frankfurt am Main, GermanyVismodegib, 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.http://www.mdpi.com/1422-0067/19/9/2485basal cell carcinomahead and neck squamous cell carcinomahedgehog signaling pathwayradiotherapy resistancevismodegib (GDC-0449) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stephanie Hehlgans Patrick Booms Ömer Güllülü Robert Sader Claus Rödel Panagiotis Balermpas Franz Rödel Shahram Ghanaati |
spellingShingle |
Stephanie Hehlgans Patrick Booms Ömer Güllülü Robert Sader Claus Rödel Panagiotis Balermpas Franz Rödel Shahram Ghanaati Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib International Journal of Molecular Sciences basal cell carcinoma head and neck squamous cell carcinoma hedgehog signaling pathway radiotherapy resistance vismodegib (GDC-0449) |
author_facet |
Stephanie Hehlgans Patrick Booms Ömer Güllülü Robert Sader Claus Rödel Panagiotis Balermpas Franz Rödel Shahram Ghanaati |
author_sort |
Stephanie Hehlgans |
title |
Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib |
title_short |
Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib |
title_full |
Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib |
title_fullStr |
Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib |
title_full_unstemmed |
Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib |
title_sort |
radiation sensitization of basal cell and head and neck squamous cell carcinoma by the hedgehog pathway inhibitor vismodegib |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-08-01 |
description |
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. |
topic |
basal cell carcinoma head and neck squamous cell carcinoma hedgehog signaling pathway radiotherapy resistance vismodegib (GDC-0449) |
url |
http://www.mdpi.com/1422-0067/19/9/2485 |
work_keys_str_mv |
AT stephaniehehlgans radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib AT patrickbooms radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib AT omergullulu radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib AT robertsader radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib AT clausrodel radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib AT panagiotisbalermpas radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib AT franzrodel radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib AT shahramghanaati radiationsensitizationofbasalcellandheadandnecksquamouscellcarcinomabythehedgehogpathwayinhibitorvismodegib |
_version_ |
1725205651283509248 |