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Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe

Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved...

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Autores principales: Pietrobono, Silvia, Santini, Roberta, Gagliardi, Sinforosa, Dapporto, Francesca, Colecchia, David, Chiariello, Mario, Leone, Cosima, Valoti, Massimo, Manetti, Fabrizio, Petricci, Elena, Taddei, Maurizio, Stecca, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833413/
https://www.ncbi.nlm.nih.gov/pubmed/29396391
http://dx.doi.org/10.1038/s41419-017-0142-0
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author Pietrobono, Silvia
Santini, Roberta
Gagliardi, Sinforosa
Dapporto, Francesca
Colecchia, David
Chiariello, Mario
Leone, Cosima
Valoti, Massimo
Manetti, Fabrizio
Petricci, Elena
Taddei, Maurizio
Stecca, Barbara
author_facet Pietrobono, Silvia
Santini, Roberta
Gagliardi, Sinforosa
Dapporto, Francesca
Colecchia, David
Chiariello, Mario
Leone, Cosima
Valoti, Massimo
Manetti, Fabrizio
Petricci, Elena
Taddei, Maurizio
Stecca, Barbara
author_sort Pietrobono, Silvia
collection PubMed
description Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds. Here, we show that the two acylguanidine analogs, compound (1) and its novel fluoride derivative (2), strongly reduce growth and self-renewal of melanoma cells, inhibiting the level of the HH signaling target GLI1 in a dose-dependent manner. Both compounds induce apoptosis and DNA damage through the ATR/CHK1 axis. Mechanistically, they prevent G2 to M cell cycle transition, and induce signs of mitotic aberrations ultimately leading to mitotic catastrophe. In a melanoma xenograft mouse model, systemic treatment with 1 produced a remarkable inhibition of tumor growth without body weight loss in mice. Our data highlight a novel route for cell death induction by SMO inhibitors and support their use in therapeutic approaches for melanoma and, possibly, other types of cancer with active HH signaling.
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spelling pubmed-58334132018-03-16 Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe Pietrobono, Silvia Santini, Roberta Gagliardi, Sinforosa Dapporto, Francesca Colecchia, David Chiariello, Mario Leone, Cosima Valoti, Massimo Manetti, Fabrizio Petricci, Elena Taddei, Maurizio Stecca, Barbara Cell Death Dis Article Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds. Here, we show that the two acylguanidine analogs, compound (1) and its novel fluoride derivative (2), strongly reduce growth and self-renewal of melanoma cells, inhibiting the level of the HH signaling target GLI1 in a dose-dependent manner. Both compounds induce apoptosis and DNA damage through the ATR/CHK1 axis. Mechanistically, they prevent G2 to M cell cycle transition, and induce signs of mitotic aberrations ultimately leading to mitotic catastrophe. In a melanoma xenograft mouse model, systemic treatment with 1 produced a remarkable inhibition of tumor growth without body weight loss in mice. Our data highlight a novel route for cell death induction by SMO inhibitors and support their use in therapeutic approaches for melanoma and, possibly, other types of cancer with active HH signaling. Nature Publishing Group UK 2018-02-02 /pmc/articles/PMC5833413/ /pubmed/29396391 http://dx.doi.org/10.1038/s41419-017-0142-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pietrobono, Silvia
Santini, Roberta
Gagliardi, Sinforosa
Dapporto, Francesca
Colecchia, David
Chiariello, Mario
Leone, Cosima
Valoti, Massimo
Manetti, Fabrizio
Petricci, Elena
Taddei, Maurizio
Stecca, Barbara
Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
title Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
title_full Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
title_fullStr Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
title_full_unstemmed Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
title_short Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
title_sort targeted inhibition of hedgehog-gli signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833413/
https://www.ncbi.nlm.nih.gov/pubmed/29396391
http://dx.doi.org/10.1038/s41419-017-0142-0
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