Novel smoothened antagonists as anti‐neoplastic agents for the treatment of osteosarcoma. Issue 6 (15th January 2018)

• Record Type: Journal Article
• Authors: Bernardini, Giulia; Geminiani, Michela; Gambassi, Silvia; Orlandini, Maurizio; Petricci, Elena; Marzocchi, Barbara; Laschi, Marcella; Taddei, Maurizio; Manetti, Fabrizio; Santucci, Annalisa
• Is Part Of: Journal of cellular physiology. Volume 233:Issue 6(2018:Jun.)
• Page Start: 4961
• Page End: 4971
• Publication Date: 2018-01-15
• Subjects: apoptosis -- cancer -- CyQuant -- GLI‐1 -- hedgehog pathway -- osteosarcoma -- research resource identifiers—RRID -- SMO inhibitors; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.26330
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : Osteosarcoma (OS) is an ultra‐rare highly malignant tumor of the skeletal system affecting mainly children and young adults and it is characterized by an extremely aggressive clinical course. OS patients are currently treated with chemotherapy and complete surgical resection of cancer tissue. However, resistance to chemotherapy and the recurrence of disease, as pulmonary metastasis, remain the two greatest challenges in the management, and treatment of this tumor. For these reasons, it is of primary interest to find alternative therapeutic strategies for OS. Dysregulated Hedgehog signalling is involved in the development of various types of cancers including OS. It has also been implicated in tumor/stromal interaction and cancer stem cell biology, and therefore presents a novel therapeutic strategy for cancer treatment. In our work, we tested the activity of five potent Smoothened (SMO) inhibitors, four acylguanidine and one acylthiourea derivatives, against an OS cell line. We found that almost all our compounds were able to inhibit OS cells proliferation and to reduce Gli1 protein levels. Our results also indicated that SMO inhibition in OS cells by such compounds, induces apoptosis with a nanomolar potency. These findings suggest that inactivation of SMO may be a useful approach to the treatment of patients with OS. Abstract : Hedgehog (Hh) pathway seems to be involved in the osteosarcoma (OS) malignant phenotype. In the present study, we present novel SMO antagonists able to modulate Hh pathway in OS cells, and evaluate the anti‐proliferative and pro‐apoptotic activity of such compounds.