Novel smoothened antagonists as anti-neoplastic agents for the treatment of osteosarcoma.

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.

journal_name

J Cell Physiol

authors

Bernardini G,Geminiani M,Gambassi S,Orlandini M,Petricci E,Marzocchi B,Laschi M,Taddei M,Manetti F,Santucci A

doi

10.1002/jcp.26330

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

4961-4971

issue

6

eissn

0021-9541

issn

1097-4652

journal_volume

233

pub_type

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