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Limited data exists regarding the combination of Hedgehog signaling (Hh) inhibition and radiotherapy, even though there are several indications that this might be a promising treatment strategy. In this study, we evaluated the combination of two Hh inhibitors, the SMO inhibitor GDC-0449 and the GLI inhibitor GANT61 with radiotherapy in different prostate cancer (PCa) models. In vitro, GANT61 was able to sensitize 22Rv1 PCa cells but not PC3 and DU145 PCa cells. The lack of radiosensitization in the latter cell lines was shown to be dependent on the presence of mutated p53. Introduction of WT p53 into PC3 cells resulted in radiosensization following GANT61 treatment, suggesting that the p53 transcription factor plays an important role in the GANT61-induced radiosensitization in vitro. Targeting at the level of SMO (GDC-0449) did not show cytotoxicity or synergy with radiation. Furthermore, we confirmed the radiosensitization effect of GANT61 in two in vivo xenograft PCa models. The decrease in tumor growth was associated with decreased proliferation and increased apoptosis. In conclusion, we provide evidence that GANT61 in combination with radiation treatment might represent a promising therapeutic strategy for enhancing the radiation response of PCa patients.

Original publication

DOI

10.18632/oncotarget.12483

Type

Journal article

Journal

Oncotarget

Publication Date

20/12/2016

Volume

7

Pages

84286 - 84298

Keywords

GANT61, Hedgehog pathway, prostate cancer, radiotherapy, xenograft mouse model, Animals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Hedgehog Proteins, Humans, Male, Mice, Inbred Strains, Mice, Nude, Mutation, Prostatic Neoplasms, Pyridines, Pyrimidines, Radiation Tolerance, Radiation, Ionizing, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays