Novel Approach to the Hedgehog Signaling Pathway: Combined Treatment of SMO and PTCH Inhibitors

Purpose: Abnormal Sonic Hedgehog signaling Pathway (Shh) activation is crucial for development of cancer stem cells, neoplastic growth and epithelial-mesenchymal transition processes in adulthood. Activation of Hedgehog signaling pathway may induces the changes in cilia found in the cell membrane, iniciates the Gli1 transcription factor that is translocated to the cell nucleus and finally, the target genes are transcribed. In this study, invastigation of the antiproliferative, anti-invasive and antimigrative effect of the combined use of robotnikinin (Ptch1 antagonist) and vismodegib (Smo inhibitor) on the hedgehog signaling pathway was aimed. Material and Methods: After demonstarting the presence of the hedgehog signaling pathway in the glioblastoma cell line U87-MG, the effect of the combined use of the robotnikinin and the vismodegib on the hedgehog signaling pathway was investigated. In-vitro cell proliferation, migration, and invasion analysis of the combination of antagonist and inhibitor and in silico drug-likeness analysis were performed. Results: Two different combinations of robotnikinin and vismodegib were tested. In vitro studies show that the combined use of agents in combined treatments of Smo and Ptch1is more effective than their individual usage. Conclusion: Inhibition of the hedgehog signaling pathway with specific inhibitors and antagonists is considered an innovative strategy for cancer therapy.