The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas

Abstract Glioblastoma multiforme is the most common primary brain tumor and among the most lethal types of cancer. Several mono-target small molecule-inhibitors have been investigated as novel therapeutics, thus far with poor success. In this study we investigated the anticancer effects of SB747651A...

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Autores principales:	Arnon Møldrup Knudsen, Henning Bünsow Boldt, Elisabeth Victoria Jakobsen, Bjarne Winther Kristensen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eb0995e2ff9d49fc8f512f48a138a289
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spelling	oai:doaj.org-article:eb0995e2ff9d49fc8f512f48a138a2892021-12-02T13:18:08ZThe multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas10.1038/s41598-021-85536-42045-2322https://doaj.org/article/eb0995e2ff9d49fc8f512f48a138a2892021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85536-4https://doaj.org/toc/2045-2322Abstract Glioblastoma multiforme is the most common primary brain tumor and among the most lethal types of cancer. Several mono-target small molecule-inhibitors have been investigated as novel therapeutics, thus far with poor success. In this study we investigated the anticancer effects of SB747651A, a multi-target small-molecule inhibitor, in three well characterized patient-derived glioblastoma spheroid cultures and a murine orthotopic xenograft model. Concentrations of 5–10 µM SB747651A reduced cell proliferation, spheroid formation, migration and chemoresistance, while apoptotic cell death increased. Investigation of oncogenic kinase signaling showed decreased phosphorylation levels of mTOR, CREB, GSK3 and GYS1 leading to altered glycogen metabolism and formation of intracellular reactive oxygen species. Expression levels of cancer stemness marker SOX2 were reduced in treated tumor cells and SB747651A treatment significantly prolonged survival of mice with intracranial glioblastoma xenografts, while no adverse effects were observed in vivo at doses of 25 mg/kg administered 5 days/week for 8 weeks. These findings suggest that SB747651A has anticancer effects in glioblastoma. The cancer-related pathophysiological mechanisms targeted by SB747651A are shared among many types of cancer; however, an in-depth clarification of the mechanisms of action in cancer cells is important before further potential application of SB747651A as an anticancer agent can be considered.Arnon Møldrup KnudsenHenning Bünsow BoldtElisabeth Victoria JakobsenBjarne Winther KristensenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arnon Møldrup Knudsen Henning Bünsow Boldt Elisabeth Victoria Jakobsen Bjarne Winther Kristensen The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas
description	Abstract Glioblastoma multiforme is the most common primary brain tumor and among the most lethal types of cancer. Several mono-target small molecule-inhibitors have been investigated as novel therapeutics, thus far with poor success. In this study we investigated the anticancer effects of SB747651A, a multi-target small-molecule inhibitor, in three well characterized patient-derived glioblastoma spheroid cultures and a murine orthotopic xenograft model. Concentrations of 5–10 µM SB747651A reduced cell proliferation, spheroid formation, migration and chemoresistance, while apoptotic cell death increased. Investigation of oncogenic kinase signaling showed decreased phosphorylation levels of mTOR, CREB, GSK3 and GYS1 leading to altered glycogen metabolism and formation of intracellular reactive oxygen species. Expression levels of cancer stemness marker SOX2 were reduced in treated tumor cells and SB747651A treatment significantly prolonged survival of mice with intracranial glioblastoma xenografts, while no adverse effects were observed in vivo at doses of 25 mg/kg administered 5 days/week for 8 weeks. These findings suggest that SB747651A has anticancer effects in glioblastoma. The cancer-related pathophysiological mechanisms targeted by SB747651A are shared among many types of cancer; however, an in-depth clarification of the mechanisms of action in cancer cells is important before further potential application of SB747651A as an anticancer agent can be considered.
format	article
author	Arnon Møldrup Knudsen Henning Bünsow Boldt Elisabeth Victoria Jakobsen Bjarne Winther Kristensen
author_facet	Arnon Møldrup Knudsen Henning Bünsow Boldt Elisabeth Victoria Jakobsen Bjarne Winther Kristensen
author_sort	Arnon Møldrup Knudsen
title	The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas
title_short	The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas
title_full	The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas
title_fullStr	The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas
title_full_unstemmed	The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas
title_sort	multi-target small-molecule inhibitor sb747651a shows in vitro and in vivo anticancer efficacy in glioblastomas
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/eb0995e2ff9d49fc8f512f48a138a289
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The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas

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