Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells

Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment o...

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Autores principales:	Wioleta Justyna Omeljaniuk, Rafał Krętowski, Wioletta Ratajczak-Wrona, Ewa Jabłońska, Marzanna Cechowska-Pasko
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	apoptosis glioblastoma dual PI3K/mTOR inhibitor GDC-0980 apitolisib Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/3cf5758e31d84f4ba9ce103308bb4141
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spelling	oai:doaj.org-article:3cf5758e31d84f4ba9ce103308bb41412021-11-11T16:58:20ZNovel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells10.3390/ijms2221115111422-00671661-6596https://doaj.org/article/3cf5758e31d84f4ba9ce103308bb41412021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11511https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment of cancer. The aim of this study was to investigate the underlying mechanism of novel dual PI3K/mTOR inhibitor, Apitolisib (GDC-0980), in A-172 and U-118-MG GBM tumour cell line suppression. It has been demonstrated that GDC-0980 induces time- and dose-dependent cytotoxicity and apoptosis in investigated glioma cell lines. In our study, the strongest induction of apoptosis was exhibited in the A-172 line after 48 h of incubation with 20 µM GDC-0980, where we observed 46.47% of apoptotic cells. In conclusion, we first discovered that dual PI3K/mTOR blockade by GDC-0980 markedly suppressed survival of human GBM cells and induced apoptosis, independent of the ER stress-mediated DR5 activation. We suggest that GDC-0980, by exerting an inhibitory effect on PERK expression, may thus block its inhibitory effect on protein synthesis, leading to intensification of translation, and this may result in an increase in apoptosis. On the other hand, CHOP stimulates protein synthesis and increases apoptosis. These findings suggest that GDC-0980 may be a candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy.Wioleta Justyna OmeljaniukRafał KrętowskiWioletta Ratajczak-WronaEwa JabłońskaMarzanna Cechowska-PaskoMDPI AGarticleapoptosisglioblastomadual PI3K/mTOR inhibitorGDC-0980apitolisibBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11511, p 11511 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	apoptosis glioblastoma dual PI3K/mTOR inhibitor GDC-0980 apitolisib Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	apoptosis glioblastoma dual PI3K/mTOR inhibitor GDC-0980 apitolisib Biology (General) QH301-705.5 Chemistry QD1-999 Wioleta Justyna Omeljaniuk Rafał Krętowski Wioletta Ratajczak-Wrona Ewa Jabłońska Marzanna Cechowska-Pasko Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells
description	Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment of cancer. The aim of this study was to investigate the underlying mechanism of novel dual PI3K/mTOR inhibitor, Apitolisib (GDC-0980), in A-172 and U-118-MG GBM tumour cell line suppression. It has been demonstrated that GDC-0980 induces time- and dose-dependent cytotoxicity and apoptosis in investigated glioma cell lines. In our study, the strongest induction of apoptosis was exhibited in the A-172 line after 48 h of incubation with 20 µM GDC-0980, where we observed 46.47% of apoptotic cells. In conclusion, we first discovered that dual PI3K/mTOR blockade by GDC-0980 markedly suppressed survival of human GBM cells and induced apoptosis, independent of the ER stress-mediated DR5 activation. We suggest that GDC-0980, by exerting an inhibitory effect on PERK expression, may thus block its inhibitory effect on protein synthesis, leading to intensification of translation, and this may result in an increase in apoptosis. On the other hand, CHOP stimulates protein synthesis and increases apoptosis. These findings suggest that GDC-0980 may be a candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy.
format	article
author	Wioleta Justyna Omeljaniuk Rafał Krętowski Wioletta Ratajczak-Wrona Ewa Jabłońska Marzanna Cechowska-Pasko
author_facet	Wioleta Justyna Omeljaniuk Rafał Krętowski Wioletta Ratajczak-Wrona Ewa Jabłońska Marzanna Cechowska-Pasko
author_sort	Wioleta Justyna Omeljaniuk
title	Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells
title_short	Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells
title_full	Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells
title_fullStr	Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells
title_full_unstemmed	Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells
title_sort	novel dual pi3k/mtor inhibitor, apitolisib (gdc-0980), inhibits growth and induces apoptosis in human glioblastoma cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3cf5758e31d84f4ba9ce103308bb4141
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Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells

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