Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia

Abstract Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in pre...

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Autores principales:	Mattia Mori, Luca Tottone, Deborah Quaglio, Nadezda Zhdanovskaya, Cinzia Ingallina, Marisa Fusto, Francesca Ghirga, Giovanna Peruzzi, Maria Elisa Crestoni, Fabrizio Simeoni, Francesca Giulimondi, Claudio Talora, Bruno Botta, Isabella Screpanti, Rocco Palermo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d39668e761db46ddb4b089d4a0dbbce2
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spelling	oai:doaj.org-article:d39668e761db46ddb4b089d4a0dbbce22021-12-02T15:05:32ZIdentification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia10.1038/s41598-017-02316-92045-2322https://doaj.org/article/d39668e761db46ddb4b089d4a0dbbce22017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02316-9https://doaj.org/toc/2045-2322Abstract Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side-effects, limiting their widespread therapeutic use. Here, by functional and biological analysis of the most representative molecules of an in house library of natural products, we have designed and synthetized the chalcone-derivative 8 possessing Notch inhibitory activity at low micro molar concentration in T-ALL cell lines. Structure-activity relationships were afforded for the chalcone scaffold. Short term treatments with compound 8 resulted in a dose-dependent decrease of Notch signaling activity, halted cell cycle progression and induced apoptosis, thus affecting leukemia cell growth. Taken together, our data indicate that 8 is a novel Notch inhibitor, candidate for further investigation and development as an additional therapeutic option against Notch-dependent cancers.Mattia MoriLuca TottoneDeborah QuaglioNadezda ZhdanovskayaCinzia IngallinaMarisa FustoFrancesca GhirgaGiovanna PeruzziMaria Elisa CrestoniFabrizio SimeoniFrancesca GiulimondiClaudio TaloraBruno BottaIsabella ScrepantiRocco PalermoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mattia Mori Luca Tottone Deborah Quaglio Nadezda Zhdanovskaya Cinzia Ingallina Marisa Fusto Francesca Ghirga Giovanna Peruzzi Maria Elisa Crestoni Fabrizio Simeoni Francesca Giulimondi Claudio Talora Bruno Botta Isabella Screpanti Rocco Palermo Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia
description	Abstract Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side-effects, limiting their widespread therapeutic use. Here, by functional and biological analysis of the most representative molecules of an in house library of natural products, we have designed and synthetized the chalcone-derivative 8 possessing Notch inhibitory activity at low micro molar concentration in T-ALL cell lines. Structure-activity relationships were afforded for the chalcone scaffold. Short term treatments with compound 8 resulted in a dose-dependent decrease of Notch signaling activity, halted cell cycle progression and induced apoptosis, thus affecting leukemia cell growth. Taken together, our data indicate that 8 is a novel Notch inhibitor, candidate for further investigation and development as an additional therapeutic option against Notch-dependent cancers.
format	article
author	Mattia Mori Luca Tottone Deborah Quaglio Nadezda Zhdanovskaya Cinzia Ingallina Marisa Fusto Francesca Ghirga Giovanna Peruzzi Maria Elisa Crestoni Fabrizio Simeoni Francesca Giulimondi Claudio Talora Bruno Botta Isabella Screpanti Rocco Palermo
author_facet	Mattia Mori Luca Tottone Deborah Quaglio Nadezda Zhdanovskaya Cinzia Ingallina Marisa Fusto Francesca Ghirga Giovanna Peruzzi Maria Elisa Crestoni Fabrizio Simeoni Francesca Giulimondi Claudio Talora Bruno Botta Isabella Screpanti Rocco Palermo
author_sort	Mattia Mori
title	Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia
title_short	Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia
title_full	Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia
title_fullStr	Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia
title_full_unstemmed	Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia
title_sort	identification of a novel chalcone derivative that inhibits notch signaling in t-cell acute lymphoblastic leukemia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d39668e761db46ddb4b089d4a0dbbce2
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Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia

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